Combination therapy

ABSTRACT

Provided herein are methods of treating diseases, such as cancer, using a combination therapy. In certain embodiments, the methods comprise administering an effective amount of a phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount of a PD-1 or PD-L1 inhibitor to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 16/613,638,filed Nov. 14, 2019, which is a national stage entry ofPCT/US2018/033936, filed on May 22, 2018, and claims benefit of U.S.Patent Application No. 62/510,204, filed on May 23, 2017, and U.S.Patent Application No. 62/518,359, filed on Jun. 12, 2017, which are allhereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Phosphoinositide-3-kinases (PI3Ks) play a variety of roles in normaltissue physiology (Foukas & Shepherd, Biochem. Soc. Trans. 2004, 32,330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), with p110α having aspecific role in cancer growth, p110β in thrombus formation mediated byintegrin α_(II)β₃ (Jackson et al., Nat. Med. 2005, 11, 507), and p110γ,in inflammation, rheumatoid arthritis, and other chronic inflammationstates (Barber et al., Nat. Med. 2005, 11, 933; Camps et al., Nat. Med.2005, 11, 936; Rommel et al., Nat. Rev. 2007, 7, 191; and Ito, et al.,J. Pharm. Exp. Therap. 2007, 321, 1). Inhibitors of PI3Ks havetherapeutic potential in the treatment of various proliferativediseases, including cancer.

SUMMARY OF THE DISCLOSURE INVENTION

Disclosed herein is a method for treating or preventing a diseasecomprising administering:

(i) an effective amount of a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c), wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c); —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1c)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5c) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(=NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1, and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c),R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), and R^(5g) isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) oxo,cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with one,two, three, or four substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one, two, three, or four substituents Q^(a);or (iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, which is further optionally substituted withone, two, three, or four substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(c)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl; or

wherein two substituents Q that are adjacent to each other optionallyform a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and

(ii) an effective amount of a PD-1 inhibitor or PD-L1 inhibitor to apatient,

In some embodiments, R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, orheteroaryl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

In some embodiments, R^(5a) and R^(5b) are each independently (a) halo;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

In some embodiments, R^(5a) and R^(5b) are each methyl, optionallysubstituted with one, two or three halo(s). In some embodiments, n is 1.In some embodiments, n is 1 and R^(5f) and R^(5g) are each hydrogen. Insome embodiments, n is 0. In some embodiments, m is 0.

In some embodiments, the compound of Formula (I) is of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one, two, three, or foursubstituents Q^(a).

In some embodiments, the compound of Formula (I) is Compound I:

an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound II:

an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound III:

an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound IV:

an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound V:

an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the PD-1 or PD-L1 inhibitor is pidilizumab,nivolumab, pembrolizumab, atezolizumab, avelumab, BMS-936559, durvalumabor a combination thereof. In some embodiments, the PD-1 or PD-L1inhibitor is pidilizumab, nivolumab, pembrolizumab, atezolizumab,avelumab, BMS-936559, BGB-A317, PDR001, REGN2810, durvalumab or acombination thereof.

In some embodiments, the disease being treated is cancer.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the invention are utilized, andthe accompanying drawings of which:

FIG. 1 illustrates the Kaplan-Meier survival curves obtained fromExample 2a, wherein a study was performed evaluating the efficacy of acombination treatment of Compound I and a PD-1 inhibitor (RPMI-14), in aMC38 murine adenocarcinoma model. The figure depicts the efficacy of twocycles of the combination treatment in comparison to a single cycle of acombination treatment or a single cycle of the PD-1 inhibitor.

FIG. 2 illustrates the Kaplan-Meier survival curves obtained fromExample 2a, wherein a study was performed evaluating the efficacy of acombination treatment of Compound I and the PD-1 inhibitor (RPM1-14) ina MC38 murine adenocarcinoma model. The figure depicts the efficacy oftwo cycles of the combination treatment in comparison to a single cycleof a combination treatment or a single cycle of the combination with anadditional cycle of Compound I.

FIG. 3 illustrates the Kaplan-Meier survival curves obtained fromExample 2a, wherein a study was performed evaluating the efficacy of acombination treatment of Compound I and the PD-1 inhibitor (RPM1-14) ina MC38 murine adenocarcinoma model. The figure depicts the efficacy oftwo cycles of the combination treatment in comparison to a single cycleof a combination treatment or a single cycle of the combination with anadditional cycle of the PD-1 inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are pharmaceutical compositions comprising a PI3Kinhibitor and a PD-1 or a PD-L1 inhibitor. In some instances, thepharmaceutical compositions described herein may be used for treatingdiseases or disorders associated with excessive cell proliferation, suchas cancer. Also described herein are methods of treating theproliferative diseases and disorders with i) a PI3K inhibitor; and ii) aPD-1 or a PD-L1 inhibitor.

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs. The term“subject” refers to an animal, including, but not limited to, a primate(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, ormouse. The terms “subject” and “patient” are used interchangeably hereinin reference, for example, to a mammalian subject, such as a humansubject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The terms “therapeutically effective amount” and “effective amount” aremeant to include the amount of a compound that, when administered, issufficient to prevent development of, or alleviate to some extent, oneor more of the symptoms of the disorder, disease, or condition beingtreated. The terms “therapeutically effective amount” or “effectiveamount” also refer to the amount of a compound that is sufficient toelicit the biological or medical response of a biological molecule(e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, orhuman, which is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” and“physiologically acceptable excipient” refer to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: theScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2009.

The terms “about” and “approximately” mean an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the terms “about” and “approximately” mean within1, 2, 3, or 4 standard deviations. In certain embodiments, the terms“about” and “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition. As used herein, “active ingredient” and “active substance”may be an optically active isomer of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder, disease, or condition.

The terms “naturally occurring” and “native” when used in connectionwith biological materials such as nucleic acid molecules, polypeptides,host cells, and the like, refer to materials which are found in natureand are not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “PI3K” refers to a phosphoinositide 3-kinase or variantthereof, which is capable of phosphorylating the inositol ring of PI inthe D-3 position. The term “PI3K variant” is intended to includeproteins substantially homologous to a native PI3K, i.e., proteinshaving one or more naturally or non-naturally occurring amino aciddeletions, insertions, or substitutions (e.g., PI3K derivatives,homologs, and fragments), as compared to the amino acid sequence of anative PI3K. The amino acid sequence of a PI3K variant is at least about80% identical, at least about 90% identical, or at least about 95%identical to a native PI3K. Examples of PI3K include, but are notlimited to, p110α, p110α, p110δ, p110γ, PI3K-C2α, PI3K-C2β, PI3K-C2γ,Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res.1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ksare classified into at least four classes. Class I includes p110α,p110β, p110δ, and p110γ. Class II includes PI3K-C2α, PI3K-C2β, andPI3K-C2γ. Class III includes Vps34. Class IV includes mTOR, ATM, ATR,and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. Incertain embodiments, the PI3K is p110α, p110β, or p110γ. In certainembodiments, the PI3K is a variant of a Class I kinase. In certainembodiments, the PI3K is a p110α mutant. Examples of p110α mutantsinclude, but are not limited to, R38H, G106V, K111N, K227E, N345K,C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P,I800L, T1025S, M10431, M1043V, H1047L, H1047R, and H1047Y (Ikenoue etal., Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al., Proc. Natl.Acad Sci., 2007, 104, 5569-5574). In certain embodiments, the PI3K is a,Class II kinase. In certain embodiments, the PI3K is PI3K-C2α, PI3K-C2β,or PI3K-C2γ. In certain embodiments, the PI3K is a Class III kinase. Incertain embodiments, the PI3K is Vps34. In certain embodiments, the PI3Kis a Class IV kinase. In certain embodiments, the PI3K, is mTOR, ATM,ATR, or DNA-PK.

The term “PD-1” refers to programmed cell death-1 receptor or programmedcell death protein 1, also known as cluster of differentiation 279(CD279). The PD-1 protein in humans is encoded by the PDCD1 gene. PD-1is a cell surface receptor that plays an important role indown-regulating the immune system and promoting self tolerance bysuppressing T cell inflammatory activity. PD-1 is expressed on thesurface of activated T cells and guards against autoimmunity through adual mechanism of promoting apoptosis (programmed cell death) in antigenspecific T-cells in lymph nodes while simultaneously reducing apoptosisin regulatory T cells (anti-inflammatory, suppressive T cells. PD-1inhibitors activate the immune system to attack tumors and are thereforeused to treat some types of cancer.

The term “PD-L1” refers to programed death-ligand 1 also known ascluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1). PD-L1 isa protein encoded by the CD274 gene. PD-L1 is a transmembrane proteinthat plays a major role in suppressing the immune system. PD-L1 binds toits receptor, PD-1 (found on activated T cells, B cells, and myeloidcells) to modulate activation or inhibition of T cell responses. PD-L1,the ligand for PD-1, is highly expressed in several cancers. Inhibitionof the interaction between PD-1 and PD-L1 can enhance T-cell responsesagainst cancer cells or tumors, and thus be useful for the treatment ofcancer.

The terms “synergy,” “synergism,” and “synergistic” as used herein referto a combination of therapies (e.g., use of a PI3K inhibitor of Formula(I) and a PD-1 inhibitor or PD-L1 inhibitor) that is more effective thanthe expected additive effects of any two or more single therapies. Forexample, a synergistic effect of a combination of therapies permits theuse of lower dosages of one or more of the therapies and/or lessfrequent administration of said therapies to a subject. The ability toutilize lower dosages of therapies and/or to administer the therapiesless frequently reduces the toxicity associated with the administrationof the therapies to a subject without reducing the efficacy of saidtherapies in the prevention, management, treatment, or amelioration of agiven disease, such as an autoimmune disease, inflammatory disease, orcancer including, but not limited to, chronic lymphocytic leukemia ornon-Hodgkin's lymphoma. In addition, a synergistic effect can result inimproved efficacy of therapies in the prevention, management, treatment,or amelioration of a given disease, such an autoimmune disease,inflammatory disease, or cancer including, but not limited to, chroniclymphocytic leukemia or non-Hodgkin's lymphoma. Finally, synergisticeffects of a combination of therapies may avoid or reduce adverse orunwanted side effects associated with the use of any single therapy. The“synergy,” “synergism,” or “synergistic” effect of a combination may bedetermined herein by the methods of Chou et al., and/or Clarke et al.See Ting-Chao Chou, Theoretical Basis, Experimental Design, andComputerized Simulation of Synergism and Antagonism in Drug CombinationStudies, Pharmacol Rev 58:621-681 (2006), and Clarke et al., issues inexperimental design and endpoint analysis in the study of experimentalcytotoxic agents in vivo in breast cancer and other models, BreastCancer Research and Treatment 46:255-278 (1997), which are bothincorporated by reference for the methods of determining the “synergy,”synergism,” or “synergistic” effect of a combination.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-A (¹⁴N), nitrogen-15 (¹⁵N),oxygen-A (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O),oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F), phosphorus-31(³⁵S), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S),sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S),chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125 (¹²⁵I),iodine-127 (¹²⁷I) iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). In certainembodiments, an “isotopic variant” of a compound is in a stable form,that is, non-radioactive. In certain embodiments, an “isotopic variant”of a compound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), carbon-12(¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16(¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31(³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), Chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I) and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, for example, or any carboncan be ¹³C. for example, or any nitrogen can be ¹⁵N, for example, or anyoxygen can be ¹⁸O, for example, where feasible according to the judgmentof one of skill. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of deuterium (D).

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. The term “alkyl”also encompasses both linear and branched alkyl, unless otherwisespecified. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and brandied C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms). For example, C₁₋₆ alkyl refers to alinear saturated monovalent hydrocarbon radical of 1 to 6 carbon atomsor a branched saturated monovalent hydrocarbon radical of 3 to 6 carbonatoms.

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. The term “alkylene”encompasses both linear and branched alkylene, unless otherwisespecified. In certain embodiments, the alkylene is a linear saturateddivalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅),1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturateddivalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆and branched C₃₋₆ alkylene groups are also referred as “lower alkylene.”Examples of alkylene groups include, but are not limited to, methylene,ethylene, propylene (including all isomeric forms), n-propylene,isopropylene, butylene (including all isomeric forms), n-butylene,isobutylene, t-butylene, pentylene (including all isomeric forms), andhexylene (including all isomeric forms). For example, C₁₋₆ alkylenerefers to a linear saturated divalent hydrocarbon radical of 1 to 6carbon atoms or a branched saturated divalent hydrocarbon radical of 3to 6 carbon atoms.

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Forexample, C₁₋₆ heteroalkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—, —CH₂NHCH₂—,—CH₂CH₂NH—, —CH₂S—, —CH₂SCH₂—, and —CH₂CH₂S—. In certain embodiments,heteroalkylene may also be optionally substituted with one or moresubstituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one, carbon-carbon double bond(s).The alkenyl may be optionally substituted with one or more substituentsQ as described herein. The term “alkenyl” also embraces radicals having“cis” and “trans” configurations, or alternatively, “Z” and “E”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one, carbon-carbondouble bond(s). The alkenylene may be optionally substituted with one ormore substituents Q as described herein. Similarly, the term“alkenylene” also embraces radicals having “cis” and “trans”configurations, or alternatively, “E” and “Z” configurations. As usedherein, the term “alkenylene” encompasses both linear and branchedalkenylene, unless otherwise specified. For example, C₂₋₆ alkenylenerefers to a linear unsaturated divalent hydrocarbon radical of 2 to 6carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3to 6 carbon atoms. In certain embodiments, the alkenylene is a lineardivalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene propenylene,butenylene, and 4-methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one, carbon-carbondouble bond(s), and which contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Theheteroalkenylene may be optionally substituted with one or moresubstituents Q as described herein. The term “heteroalkenylene” embracesradicals having a “cis” or “trans” configuration or a mixture thereof,or alternatively, a “Z” or “E” configuration or a mixture thereof, asappreciated by those of ordinary skill in the art. For example, C₂₋₆heteroalkenylene refers to a linear unsaturated divalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated divalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, theheteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examplesof heteroalkenylene groups include, but are not limited to, —CH═CHO—,—CH═CHOCH₂—, —CH═CHCH₂O—, —CH═CHS—, —CH═CHSCH₂—, —CH═CHCH₂S—, or—CH═CHCH₂NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one, carbon-carbon triple bond(s).The alkynyl may be optionally substituted with one or more substituentsQ as described herein. The term “alkynyl” also encompasses both linearand branched alkynyl, unless otherwise specified. In certainembodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀),3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms.Examples of alkynyl groups include, but are not limited to, ethynyl(—C≡CH) and propargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to alinear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms.

The term “cycloalkyl” refers to a cyclic saturated bridged and/ornon-bridged monovalent hydrocarbon radical, which may be optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, the cycloalkyl has from 3 to 20 (C₃₋₂₀), from3 to15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “cycloalkenyl” refers to a cyclic unsaturated, nonaromaticbridged and/or non-bridged monovalent hydrocarbon radical, which may beoptionally substituted with one or more substituents Q as describedherein. In certain embodiments, the cycloalkenyl has from 3 to 20(C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7(C₃₋₇) carbon atoms. Examples of cycloalkyl groups include, but are notlimited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl,

The term “aryl” refers to a monocyclic aromatic group and/or multicyclicmonovalent aromatic group that contain at least one aromatic hydrocarbonring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples of arylgroups include, but are not limited to, phenyl, naphthyl, fluorenyl,azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Arylalso refers to bicyclic or tricyclic carbon rings, where one of therings is aromatic and the others of which may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be optionally substituted with one or more substituents Q asdescribed herein.

The terms “aralkyl” and “arylalkyl” refer to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearalkyl has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16(C₇₋₁₆) carbon atoms. Examples of aralkyl groups include, but are notlimited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certainembodiments, the aralkyl are optionally substituted with one or moresubstituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contain at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, N, and P in the ring. Aheteroaryl group is bonded to the rest of a molecule through itsaromatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, one to four N atoms, and/or one or two Patoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. Examples of monocyclic heteroaryl groups include, but arenot limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl,tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroarylgroups include, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl may also be optionally substituted with one or moresubstituents Q as described herein as described herein.

The terms “heterocyclyl” and “heterocyclic” refer to a monovalentmonocycle non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, N, and P; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. A heterocyclyl group is bonded to the rest of a moleculethrough its non-aromatic ring. In certain embodiments, the heterocyclylis a monocycle, bicyclic, tricyclic, or tetracyclic ring system, whichmay be spiro, fused, or bridged, and in which nitrogen or sulfur atomsmay be optionally oxidized, nitrogen atoms may be optionallyquaternized, and some rings may be partially or fully saturated, oraromatic. The heterocyclyl may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Examples of such heterocyclic groups include, but are notlimited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl may alsobe optionally substituted with one or more substituents Q as describedherein.

The terms “halogen,” “halide,” and “halo” refer to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl,aralkyl, heteroaryl, heteroaryl-C₁₋₆ alkyl, and heterocyclyl group, maybe substituted with one or more substituents Q, each of which isindependently selected from, e.g., (a) oxo (═O), halo, cyano (—CN), andnitro (—NO₂); (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl,each of which is further optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q^(a); and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q_(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a). As usedherein, all groups that can be substituted are “optionally substituted,”unless otherwise specified.

In one embodiment, each substituent Q^(a) is independently selected fromthe group consisting of (a) oxo, cyano, halo, and nitro; and (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h),—P(O)(OR^(e))R^(h), —P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (ii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

In certain embodiments, “optically active” and “enantiomerically pure”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof the desired enantiomer and about 5% or less of the less preferredenantiomer based on the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof”has the same meaning as the phrase “an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant of the compound referenced therein; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug of the compound referencedtherein; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug of an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, or an isotopic variant of the compound referencedtherein.”

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in a stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

Compounds

Disclosed herein are PI3K inhibitors of Formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —C(O)R^(1a), —OC(O)OR^(1a),—C(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)OR^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5d))_(n)—(C₆₋₁₄ aryl) or—(CR^(5a)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C_(hd-6) alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)OR^(1a), —OC(O)OR^(1a), —C(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),——NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(=NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c), or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c),R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), and R^(5g) isoptionally substituted with one or more, in one embodiment, one, two,three, four, or five, substituents Q, wherein each substituent Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heterocyclyl, which isfurther optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(s)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(s)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl; or

wherein two substituents Q that are adjacent to each other optionallyform a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).

In one embodiment of a compound of Formula (I),

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1e),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q as definedherein.

In another embodiment of a compound of Formula (I),

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl: or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5d)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—SO)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R_(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c), or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q as definedherein.

In yet another embodiment of a compound of Formula (1),

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R¹a, —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q as definedherein.

In still another embodiment of a compound of Formula (I),

X, Y, and Z are N:

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),—S(O)₂R^(1a), —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) whenone occurrence of R^(5f) and one occurrence of R^(5g) are attached tothe same carbon atom, the R^(5f) and R^(5g) together with the carbonatom to which they are attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q as definedherein.

Synthesis of compounds of Formula (I) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

Also provided herein is a compound of Formula (IX):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocylyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); and

R¹, R², R³, R⁴, R⁶, R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b),R^(5d), R^(5e), X, Y, and Z are each as defined herein.

Synthesis of compounds of Formula (IX) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In one embodiment, the compound of Formula (IX) has the structure ofFormula (IXa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5e), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y,and Z are each as defined herein.

Synthesis of compounds of Formula (IXa) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In another embodiment, the compound of Formula (IX) has the structure ofFormula (IXb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

Synthesis of compounds of Formula (IXb) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),one of R^(7a), r^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one, two, three, or four substituents Q^(a); in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄aryl, e.g., phenyl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heterocyclyl, e.g., 5-membered or6-membered heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpyrrolidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, R^(7a) is C₆₋₁₄ aryl, e.g., phenyl, optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone, two, three, or four substituents Q^(a); in certain embodiments,R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl))phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl; 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl,1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ;

R^(5d) and R^(5e) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one, two, three, or four substituents Q^(a).

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are each independently C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a);

R^(7b), R^(7c), R^(7d) and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH,

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (IX), (IXa), or (IXb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

Also provided herein is a compound of Formula (X):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) are each as defined herein.

Synthesis of compounds of Formula (X) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In one embodiment, the compound of Formula (X) has the structure ofFormula (Xa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) are each as defined herein.

Synthesis of compounds of Formula (Xa) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In another embodiment, the compound of Formula (X) has the structure ofFormula (Xb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) are each as defined herein.

Synthesis of compounds of Formula (Xb) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb), oneof R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heteroaryl, e.g., 5-membered or 6-membered heteroaryl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-4-yl, 2-methylpyridin-4-yl,2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl , 2-flouropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb),R^(7a) is C₆₋₁₄ aryl heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, R^(7a) is C₆₋₁₄ aryl, e.g., phenyl, optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone, two, three, or four substituents Q^(a); in certain embodiments,R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl 2-methylpyrozol-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methoxypyridin-4-yl,2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl;pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ;

R^(5d) and R^(5e) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are each independently C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen,

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formulae(X), (Xa), or (Xb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

P^(7a) is phenyl 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d) and R^(7e) are hydrogen.

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formulae (X), (Xa), or (Xb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

Also provided herein is a compound of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c); —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); and

R¹, R², R³, R⁴, R⁶, R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b),R^(5f), R^(5g), X, Y, and Z are each as defined herein.

Synthesis of compounds of Formula (XI) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In one embodiment, the compound of Formula (XI) has the structure ofFormula (XIa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

Synthesis of compounds of Formula (XIa) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In another embodiment, the compound of Formula (XI) has the structure ofFormula (XIb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

Synthesis of compounds of Formula (XIb) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),R^(5a) and R^(5b) are each independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OCC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R^(5f),R^(5g), R⁶, R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, Z, R^(1a),R^(1b), R^(1c), and R^(1d) are defined herein elsewhere.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one, two, three, or four substituents Q^(a); in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄aryl, e.g., phenyl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heterocyclyl, e.g., 5-membered or6-membered heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7c) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, R^(7a) is C₆₋₁₄ aryl, e.g, phenyl, optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone, two, three, or four substituents Q^(a); in certain embodiments,R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrazol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(5f) and R^(3g) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ; or R^(5f) and R^(5g) together with the carbon atom to which they areattached form C₁₋₁₀ cycloalkyl or heterocyclyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one, two, three, or four substituents Q^(a).

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl;

R^(5f) and R^(5g) are each independently hydrogen or C₁₋₆ alkyl; orR^(5f) and R^(5g) together with the carbon atom to which they areattached form C₁₋₁₀ cycloalkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁵ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formulae (XI), (XIa), or (XIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

Also provided herein is a compound of Formula (XVI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)are each as defined herein.

Synthesis of compounds of Formula (XVI) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In one embodiment of a compound of Formula (XVI), one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheteroaryl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, piperidinyl, or piperazinyl, each optionally substituted withone, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-flouropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment of a compound of Formula (XVI), one ofR_(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methoxypyridin-4-yl,2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl , or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment of a compound of Formula (XVI), R^(7a) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In another embodiment of a compound of Formula (XVI), R^(7a) is C₆₋₁₄aryl, which is optionally substituted with one, two, three, or foursubstituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isheteroaryl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) is5-membered or 6-membered heteroaryl, which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) is5-membered or 6-membered heterocyclyl, which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl,each optionally substituted with one, two, three, or four substituentsQ^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, four, or five substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl,

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment, the compound of Formula (XVI) has the structure ofFormula (XVIa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each asdefined herein.

Synthesis of compounds of Formula (XVIa) is described in U.S. Pat. No.9,056,852 B2, which is incorporated by reference for such disclosure.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X,Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheteroaryl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, piperidinyl, or piperazinyl, each optionally substituted withone, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyridin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment of a compound of Formula (XVIa), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is C₆₋₁₄ aryl,which is optionally substituted with one, two, three, or foursubstituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is heteroaryl,which is optionally substituted with one, two, three, or foursubstituents R_(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is 5-memberedor 6-membered heteroaryl, which is optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In one embodiment of a compound of Formula (XVIa), R^(7a) isheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is 5-memberedor 6-membered heterocyclyl, which is optionally substituted with one,two, three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In one embodiment of a compound of Formula (XVIa), R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenol, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment of a compound of Formula (XVIa), R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIa),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIa),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIa),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIa),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q_(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIa),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrrolidinyl,piperidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIa),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In another embodiment, the compound of Formula (XVI) has the structureof Formula (XVIb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each asdefined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X,Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheteroaryl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d) and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, piperidinyl, or piperazinyl, each optionally substituted withone, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment of a compound of Formula (XVIb), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one, two, three, four, or five substituents Q; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is C₆₋₁₄ aryl,which is optionally substituted with one, two, three, or foursubstituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is heteroaryl,which is optionally substituted with one, two, three, or foursubstituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is 5-memberedor 6-membered heteroaryl, which is optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In one embodiment of a compound of Formula (XVIb), R^(7a) isheterocylyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is 5-memberedor 6-membered heterocyclyl, which is optionally substituted with one,two, three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In one embodiment of a compound of Formula (XVIb), R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment of a compound of Formula (XVIb), R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7a),R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVIb),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVIb),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of compounds of Formulae (XVI), (XVIa), or (XVIb),R^(5a) and R^(5b) are each independently ((a) halo; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR¹a,—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c), and R¹, R², R³, R⁴, R⁶,R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(1a), R^(1b), R^(1c), andR^(1d) are defined herein elsewhere.

In one embodiment of a compound of any of the formulae provided herein,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyloptionally substituted with one, two, three, four, or five substituentsQ;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one, two, three, or four substituents Q^(a).

In one embodiment of a compound of any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In one embodiment of a compound of any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a);

R^(7b), R^(7c), R^(7d) and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In one embodiment of a compound of any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In one embodiment of a compound of any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen,

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In one embodiment of a compound of any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

The groups or variables, R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(5c),R^(5d), R^(5e), R^(5f), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), m, n, X,Y, and Z in any of the Formulae provided herein, e.g., Formulae (I),(IX), (X), (XI), (XVI), (IXa), (Xa), (XIa), (XVIa), (IXb), (Xb), (XIb),(XVIb), are further defined in the embodiments described herein. Allcombinations of the embodiments provided herein for such groups and/orvariables are within the scope of this disclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ iscyano. In certain embodiments, R¹ is halo. In certain embodiments, R¹ isfluoro, chloro, bromo, or iodo. In certain embodiments, R¹ is nitro. Incertain embodiments, R¹ is C₁₋₆ alkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₂₋₆ alkenyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₂₋₆ alkynyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₃₋₁₀ cycloalkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₆₋₁₄ aryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₇₋₁₅ aralkyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is heteroaryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is heterocyclyl, optionally substituted with one, two,three, four, or five substituents Q as described herein.

In certain embodiments, R¹ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(1a) is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —C(NR^(1a))NR^(1b)R^(1c), wherein R_(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₁₋₆ alkyl, wherein the alkyl is optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R¹ is methoxy, ethoxy, propoxy, isopropoxy, or3-dimethylaminopropoxy. In certain embodiments, R¹ is —OC(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—OC(O)OR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —OS(O)R^(1a), whereinR^(1d) is as defined herein. In certain embodiments, R¹ is—OS(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R¹ is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹ is —S(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R² is hydrogen. In certain embodiments, R² iscyano. In certain embodiments, R² is halo. In certain embodiments, R² isfluoro, chloro, bromo, or iodo. In certain embodiments, R² is nitro. Incertain embodiments, R² is C₁₋₆ alkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R² is C₂₋₆ alkenyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is C₂₋₆ alkynyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is C₃₋₁₀ cycloalkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R² is C₃₋₇ cycloalkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R² is C₆₋₁₄ aryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is C₇₋₁₅ aralkyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is heteroaryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is heterocyclyl, optionally substituted with one, two,three, four, or five substituents Q as described herein.

In certain embodiments, R² is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R² is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R² is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₁₋₆ alkyl, wherein the alkyl is optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R¹ is methoxy, ethoxy, propoxy, isopropoxy, or3-dimethylaminopropoxy. In certain embodiments, R² is —OC(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R² is—OC(O)OR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R² is—OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R² is —OS(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R² is—OS(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R² is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R² is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R² is amino(—NH₂). In certain embodiments, R² is —NR^(1a)C(O)R^(1d), wherein R^(1a)and R^(1d) are each as defined herein. In certain embodiments, R² is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R² is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)S(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R² is—SR^(1a), wherein R^(1a) is as defined herein, In certain embodiments,R² is —S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —S(O)₂R^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R² is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c)are each as defined herein. In certain embodiments, R² is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R³ ishydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or2-isopropyl).

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R⁴ ishydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or2-isopropyl).

In certain embodiments, R² and R⁴ are linked together to form a bond. Incertain embodiments, R³ and R⁴ are linked together to form C₁₋₆alkylene, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R³ and R⁴are linked together to form methylene, ethylene, or propylene, eachoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R³ and R⁴ are linkedtogether to form C₁₋₆ heteroalkylene, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R³ and R⁴ are linked together to form C₂₋₆ alkenylene,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R³ and R⁴ are linkedtogether to form C₂₋₆ heteroalkenylene, optionally substituted with one,two, three, four, or five substituents Q as described herein.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R⁶ is C₁₋₆alkyl, optionally substituted with one or more, in one embodiment, one,two, or three, halo. In certain embodiments, R⁶ is C₁₋₆ alkyl,optionally substituted with one or more, in one embodiment, one, two, orthree, fluoro. In certain embodiments, R⁶ is methyl, fluoromethyl,difluoromethyl, or trifluoromethyl. In certain embodiments, R⁶ isdifluoromethyl. In certain embodiments, R⁶ is —S—C₁₋₆ alkyl, wherein thealkyl is optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R⁶ is—S(O)—C₁₋₆ alkyl, wherein the alkyl is optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R⁶ is —SO₂—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein.

In certain embodiments, R^(5a) is hydrogen. In certain embodiments,R^(5a) is not hydrogen. In certain embodiments, R^(5a) is halo. Incertain embodiments, R^(5a) is fluoro, chloro, bromo, or iodo. Incertain embodiments, R^(5a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5a) is methyl, ethyl, propyl, or butyl, eachoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5a) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5a) is methyl. In certain embodiments, R^(5a) is C₂₋₆alkenyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5a) isC₂₋₆ alkynyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5a) isC₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, four, orfive substituents Q as described herein. In certain embodiments, R^(5a)is C₃₋₇ cycloalkyl, optionally substituted with one, two, three, four,or five substituents Q as described herein. In certain embodiments,R^(5a) is C₆₋₁₄ aryl, optionally substituted with one, two, three, four,or five substituents Q as described herein. In certain embodiments,R^(5a) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, R^(5a) is heteroaryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R^(5a) is heterocyclyl, optionally substituted with one,two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5a) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5a) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5a) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5a) is —C(O)OCH₃. In certain embodiments, R^(5a)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5a) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5a) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5a) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein, In certain embodiments, R^(5a) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5a) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5a) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is amino (—NH₂). In certainembodiments, R^(5a) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5a) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5a) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)S (O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5a) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5a) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5a) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5a) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5a) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5a) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,or heteroaryl, each of which is optionally substituted with one, two,three, four, or five substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(G)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c). In certain embodiments,R^(5a) is (a) hydrogen or halo; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl,each of which is optionally substituted with one, two, three, four, orfive substituents Q.

In certain embodiments, R^(5b) is halo. In certain embodiments, R^(5b)is fluoro, chloro, bromo, or iodo. In certain embodiments, R^(5b) isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5b) ismethyl, ethyl, propyl, or butyl, each optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5b) is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, or t-butyl. In certain embodiments, R^(5b) is methyl. Incertain embodiments, R^(5b) is C₂₋₆ alkenyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5b) is C₂₋₆ alkynyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5b) is C₃₋₁₀ cycloalkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5b) is C₃₋₇ cycloalkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5b) is C₆₋₁₄ aryl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is C₇₋₁₅ aralkyl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is heteroaryl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is heterocyclyl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is notheterocyclyl.

In certain embodiments, R^(5b) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5b) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5b) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5b) is —C(O)OCH₃. In certain embodiments, R^(5b)is C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5b) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5b) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5b) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —OC(═NR^(1a))NR^(1a)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5b) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5b) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5b) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is amino (—NH₂). In certainembodiments, R^(5b) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5b) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5b) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein, Incertain embodiments, R^(5b) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5b) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5b) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5b) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5b) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5b) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5b) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5b) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5a) and R^(5b) are each independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, eachoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5a) and R^(5b) areeach independently methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, or t-butyl, each optionally substituted with one or more halo.In certain embodiments, R^(5a) and R^(5b) are each independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5a) and R^(5b) are each methyl.

In certain embodiments, R^(5c) is C₆₋₁₄ aryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5b) is C₆₋₁₄ aryl substituted at the2-position with one substituent Q as described herein. In certainembodiments, R^(5c) is phenyl or naphthyl, each optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5c) is phenyl, naphtha-1-yl, or naphtha-2-yl,each optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5c) isphenyl, 4-chlorophenyl, 4-methoxyphenyl, or naphtha-2-yl. In certainembodiments, R^(5c) is heteroaryl, optionally substituted with one ormore substituents as described herein. In certain embodiments, R^(5c) ismonocyclic heteroaryl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) is 5-or 6-membered heteroaryl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) isbicyclic heteroaryl, optionally substituted with one or moresubstituents as described herein.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl),wherein the C₆₋₁₄aryl is optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, R^(5c) is benzyl, 2-phenethyl, 3-phenylpropyl, or4-phenylbutyl, wherein each of the phenyl moiety is optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5c) is benzyl, 2-phenethyl,3-phenylpropyl, or 4-phenylbutyl. In certain embodiments, R^(5c) isbenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, cyanobenzyl,methylbenzyl, or methoxybenzyl. In certain embodiments, R^(5c) is(naphthalen-1-yl)methyl, (naphthalen-2-yl)methyl2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl,3-(naphthalen-1-yl)propyl, 3-(naphthalen-2-yl)propyl,4-(naphthalen-1-yl)butyl, or 4-(naphthalen-2-yl)butyl, wherein each ofthe naphthyl moiety is optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, n is 0 or 1. In one embodiment, n is 1. In one embodiment,n is 1, 2, 3, or 4. In certain embodiments, R^(5c) is —CH₂—(C₆₋₁₄ aryl),wherein the C₆₋₁₄ aryl is optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, R^(5c) is —C(CH₃)₂—(C₆₋₁₄ aryl), wherein the C₆₋₁₄ aryl isoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5c) is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl or naphthyl is each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein, such as, e.g., optionally substituted with one or moreF, Cl, Br, I, —CN, —CH₃, —CF₃, —OCH₂, or —OCF₃. In certain embodiments,R^(1c) is —CH₂-phenyl, —CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, whereinthe phenyl or naphthyl is each optionally substituted with one, two,three, four, or five substituents Q as described herein, such as, e.g.,optionally substituted with one or more F, Cl, Br, I, —CN, —CH₃, —CF₃,—OCH₃, or —OCF₃. In certain embodiments, R^(5c) is —CH₂-phenyl,—CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, wherein the phenyl or naphthylis each optionally substituted with one or more F, CI, Br, I, —CN, —CH₃,—CF₃, —OCF₃. In other embodiments, R^(5c) is —CH₂-phenyl,—CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, wherein the phenyl or naphthylis each optionally substituted with one or more F, Cl, Br, I, —CN, —CH₃,—CF₃, —OCH₃, —OCF₃, —O—(C₁₋₄ alkylene)-N—(C₁₋₄ alkyl)₂ (e,g.,—O—CH₂CH₂—N(CH₃)₂), —O-heterocyclyl (e.g., —O—(N-methylpiperidinyl) or—O-piperidinyl), —O-heteroaryl (e. g., —O-pyridyl), —NH-heterocyclyl(e.g., —NH—(N-methylpiperidinyl), —NH—(N-methylpyrrolidinyl),—NH-piperidinyl, or —NH-pyrrolidinyl), —NH-heteroaryl (e.g.,—NH-pyridyl), —NCH₃-heterocyclyl (e.g., —NCH₃—(N-methylpiperidinyl),—NCH₃—(N-methylpyrrolidinyl), —NCH₃-piperidinyl, or —NCH₃-pyrrolidinyl),—NCH₃-heteroaryl (e.g., —NCH₃-pyridyl), heterocyclyl (e.g., piperidinyl,piperazinyl, N-methylpiperidinyl, or N-methylpiperazinyl), or heteroaryl(e.g., pyridyl or imidazolyl). In certain embodiments, R^(5c) is—CH₂-phenyl, —C(CH₃)₂-phenyl, —CH₂-(2-methylphenyl),—CH₂-(2-methoxylphenyl), —CH₂-(2-fluorophenyl), —CH₂-(2-chlorophenyl),—CH₂-(2-bromophenyl), —CH₂-(3-methylphenyl), —CH₂-(3-methoxylphenyl),—CH₂-(3-fluorophenyl), —CH₂-(3-chlorophenyl), —CH₂-(3-bromophenyl),—CH₂-(4-methylphenyl), —CH₂-(4-methoxylphenyl), —CH₂-(4-fluorophenyl),—CH₂-(4-chlorophenyl), —CH₂-(4-bromophenyl), —CH₂-naphtha-1-yl, or—CH₂-naphtha-2-yl.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))—(C₆₋₁₄ aryl), whereinthe C₆₋₁₄ aryl is optionally substituted with one, two, three, four, orfive substituents Q as described herein, and wherein R^(5f) and R^(5g)together with the carbon atom to which they are attached form a 3- to6-membered cycloalkyl or heterocyclyl. In one embodiment, R^(5c) is-cyclopropyl-phenyl. In one embodiment, R^(5c) is -cyclobutyl-phenyl. Inone embodiment, R^(5c) is -cyclopentyl-phenyl. In one embodiment, R^(5c)is -cyclohexyl-phenyl.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))_(n)-heteroaryl,wherein the heteroaryl is optionally substituted with one, two, three,four, or five substituents Q as described herein, wherein n is definedherein elsewhere. In certain embodiments, R^(5c) is —CH₂-(monocyclicheteroaryl), wherein the heteroaryl is optionally substituted with oneor more substituents as described herein. In certain embodiments, R^(5c)is —CH₂-(5- or 6-membered heteroaryl), wherein the heteroaryl isoptionally substituted with one or more substituents as describedherein. In certain embodiments, R^(5c) is —CH₂-(bicyclic heteroaryl),wherein the heteroaryl is optionally substituted with one or moresubstituents as described herein.

In certain embodiments, R^(5d) is hydrogen. In certain embodiments,R^(5d) is halo. In certain embodiments, R^(5d) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5d) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5d) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5d) is methyl. In certainembodiments, R^(5d) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5d) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5d) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5d) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5d) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5d) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four or five substituents Q as described herein. Incertain embodiments, R⁵ is C₇₋₁₅ aralkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(1d) is heteroaryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5d) is heterocyclyl, optionally substituted withone, two, three, four, or five substituents as described herein.

In certain embodiments, R^(5d) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5d) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5d) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(1d) is —C(O)OCH₃. In certain embodiments, R^(5d)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5d) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5d) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —OS(O)R^(1a), wherein R^(1a) as definedherein. In certain embodiments, R^(5d) is —OS(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5d) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is amino (—NH₂). In certainembodiments, R^(5d) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5d) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(1d) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c) and R^(1d) are each as defined herein. In certainembodiments, R^(5d) is —NR^(1a)S(O)R^(1d), wherein R^(1d) and R^(1d) areeach as defined herein. in certain embodiments, R^(5d) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5d) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5d) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5d) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5d) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5e) is hydrogen. In certain embodiments,R^(5e) is halo. In certain embodiments, R^(5e) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5e) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5e) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5e) is methyl. In certainembodiments, R^(5e) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5e) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5e) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5e) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5e) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5e) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5e) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5e) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5e) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5e) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5e) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5e) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5e) is —C(O)OCH₃. In certain embodiments, R^(5e)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5e) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5e) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5e) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5e) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5e) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5e) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is amino (—NH₂). In certainembodiments, R^(5e) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5e) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5e) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5e) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5e) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5e) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5e) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5e) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5e) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —S(O)₂NR_(1b)R_(1c); whereinR_(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5f) is hydrogen. In certain embodiments,R^(5f) is halo. In certain embodiments, R^(5f) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5f) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5f) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5f) is methyl. In certainembodiments, R^(5f) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5f) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5f) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5f) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5f) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5f) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5f) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5f) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5f) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5f) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is C(O)OR_(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5f) is —C(O)OCH₃. In certain embodiments, R^(5f)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —C(NR^(1a))NR^(1b)R^(1c)wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5f) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5f) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5f) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5f) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is amino (—NH₂). In certainembodiments, R^(5f) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5f) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5f) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5f) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5f) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5f) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5f) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5f) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5f) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —S(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5g) is hydrogen. In certain embodiments,R^(5g) is halo. In certain embodiments, R^(5g) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5g) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5g) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5g) is methyl. In certainembodiments, R^(5g) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5g) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5g) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5g) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5g) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5g) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5g) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5g) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5g) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5g) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5g) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5g) is —C(O)OCH₃. In certain embodiments, R^(5g)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(b), and R^(1c) are each as defined herein. In certainembodiments, R^(5g) is —OR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5g) is —OC(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —OC(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5g) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —OC(═NR^(1a))NR^(1b)R^(1c)wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5g) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5g) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is amino (—NH₂). In certainembodiments, R^(5g) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5g) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5g) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5g) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5g) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5g) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5g) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5g) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5g) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form a C₃₋₁₀cycloalkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a C₃₋₇ cycloalkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acyclopropyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclobutyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acyclopentyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclohexyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acycloheptyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclopropyl.

In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form aheterocyclyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a 3-membered heterocyclyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, when one occurrence of R^(5f)and one occurrence of R^(5g) are attached to the same carbon atom, theR^(5f) and R^(5g) together with the carbon atom to which they areattached form a 4-membered heterocyclyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form a5-membered heterocyclyl, optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, when one occurrence of R^(5f) and one occurrence of R^(5g)are attached to the same carbon atom, the R^(5f) and R^(5g) togetherwith the carbon atom to which they are attached form a 6-memberedheterocyclyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein.

In certain embodiments, R^(7a) is hydrogen. In certain embodiment,R^(7a) is cyano. In certain embodiments, R^(7a) is halo. In certainembodiments, R^(7a) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7a) is nitro. In certain embodiments, R^(7a) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7a) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is C₃₋₇ cycloalkyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7a) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7a) is phenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is phenyl, optionally substituted with one or more substituents, each ofwhich is selected independently from the group consisting of fluoro,chloro, bromo, methyl, and methoxy. In certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl. Incertain embodiments, R^(7a) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, or four substituents Q^(a) as described herein. Incertain embodiments, R^(7a) is heteroaryl, optionally substituted withone, two, three, or four substituents Q^(a) as described herein. Incertain embodiments, R^(7a) is monocyclic heteroaryl, optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(7a) is 5-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is imidazolyl or pyrozolyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7a) is imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl, or2-methylpyrozol-3-yl. In certain embodiments, R^(7a) is 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is pyridinyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, or2-methoxypyridin-4-yl. In certain embodiments, R^(7a) is heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a)as described herein. In certain embodiments, R^(7a) is monocyclicheterocyclyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is 5-membered heterocyclyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7a) is 6-membered heterocyclyl, optionally substituted with one, two,three, or four substituents Q^(a) as described herein. In certainembodiments, R^(7a) is piperidinyl or piperazinyl, optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(7a) is1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7a) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7a) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7a) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7a) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7a) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7a) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7a) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7a) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7a) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7a) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7a) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7a) is —OS(O)NR^(b)R^(b), wherein R^(b) and R^(c) areeach as defined. In herein. In certain embodiments, R^(7a) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7a) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7a) is amino(—NH₂). In certain embodiments, R^(7a) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7a) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7a) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7a) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7a) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7a) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7a) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7a) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7a) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7a) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7a) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7a) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7a) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7a) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolodin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7b) is hydrogen. In certain embodiments,R^(7b) is cyano. In certain embodiments, R^(7b) is halo. In certainembodiments, R^(7b) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7b) is nitro. In certain embodiments, R^(7b) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7b) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7b)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7b)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7b) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7b) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7b) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7b) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7b) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7b) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7b) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7b) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments. R^(7b) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments. R^(7b) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments. R^(7b) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7b) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7b) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7b) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7b) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7b) is amino(—NH₂). In certain embodiments, R^(7b) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7b) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7b) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7b) is —NR^(a)C(O)NR^(b)R^(c), wherein R^(a), R^(b),R^(c), and R^(d) are each as defined herein. In certain embodiments,R^(7b) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7b) ) is —NR^(a)S(O)₂R^(d), whereinR¹ and R^(d) are each as defined herein. In certain embodiments, R^(7b)is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7b) is—NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7b) is —SR^(a), wherein R^(a)is as defined herein. In certain embodiments, R^(7b) is —S(O)R^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7b) is—S(O)₂R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7b) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as definedherein. In certain embodiments, R^(7b) is —S(O)₂NR^(b)R^(c); whereinR^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7b) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7b) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7c) is hydrogen. In certain embodiments,R^(7c) is cyano. In certain embodiments, R^(7c) is halo. In certainembodiments, R^(7c) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7c) is nitro. In certain embodiments, R^(7c) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7c) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein, in certain embodiments, R^(7c)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7c)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7c) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7c) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments. R^(7c) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7c) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7c) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7c) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7c) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c)is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7c) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7c) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7c) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7c) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7c) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7c) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7c) is amino(—NH₂). In certain embodiments, R^(7c) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7c) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7c) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments. R^(7c) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7c) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7c) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7c) is —NR^(a)S(O)NR^(b)R^(c) wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7c) is —NR^(a)S(O)₂NR^(b)R^(c) wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7c) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7c) is—S(O)R^(a), wherein R^(a) is as defined herein, In certain embodiments,R^(7c) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —S(O)NR^(b)R^(c), wherein R^(a), R^(b), and R^(c)are each as defined herein. In certain embodiments, R^(7c) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7c) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7c) is phenyl, 2-fluorophenyl,2-chlorophenol, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7d) is hydrogen. In certain embodiments,R^(7d) is cyano. In certain embodiments, R^(7d) is halo. In certainembodiments, R^(7d) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7d) is nitro. In certain embodiments, R^(7d) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7d) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7d)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7d)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q_(a) as described herein. In certain embodiments,R^(7d) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q_(a) as described herein. In certain embodiments,R^(7d) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7d) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7d) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7d) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7d) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7d) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7d) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7d) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7d) is —OC(O)NR^(b)R^(b), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7d) is—OC(═NR^(a))NR^(b)R^(b), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7d) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7d) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7d) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7d) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7d) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7d) is amino(—NH₂), in certain embodiments, R^(7d) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7d) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7d) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7d) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7d) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7d) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7d) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7d) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7d) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7d) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7d) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7d) is 'S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7d) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7d) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7d) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7e) is hydrogen. In certain embodiments,R^(7e) is cyano. In certain embodiments, R^(7e) is halo. In certainembodiments, R^(7e) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7e) is nitro. In certain embodiments, R^(7e) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7a) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7e)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7e)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7e) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7e) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7e) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7a) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7e) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7e) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7e) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7e) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7e) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7e) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7e) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7e) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7e) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7e) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7c) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7e) is amino(—NH₂). In certain embodiments, R^(7e) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7e) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7e) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7e) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7e) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7e) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7e) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7e) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7e) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7e) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7e) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7e) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7e) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, piperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached. form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7a) andR^(7b) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7a) and R^(7b) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7a) and R^(7b)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form bicyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached form monocyclic heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7a) and R^(7b) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7a) and R^(7b) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7b) andR^(7c) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7b) and R^(7c) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7b) and R^(7c)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form bicyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form monocyclic heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7b) and R^(7c) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7b) and R^(7c) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7c) andR^(7d) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7c) and R^(7d) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7c) and R^(7d)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form bicyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form monocyclic heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7c) and R^(7d) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7c) and R^(7d) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7d) andR^(7e) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments.R^(7d) and R^(7e) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7d) and R^(7e)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form a 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form bicyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form monocyclic heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7d) and R^(7e) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7d) and R^(7e) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, m is 0. In certain embodiments, m is 1.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certainembodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or3. In certain embodiments, n is 1 or 2.

In certain embodiments, m is 0, and n is 0, 1, 2, or 3. In certainembodiments, m is 0, and n is 0, 1, or 2. In certain embodiments, m is0, and n is 0 or 1. In certain embodiments, m is 0, and n is 0. Incertain embodiments, m is 0, and n is 1. In certain embodiments, m is 1,and n is 0, 1, 2, or 3. In certain embodiments, m is 1, and n is 0, 1,or 2. In certain embodiments, m is 1, and n is 0 or 1. In certainembodiments, m is 1, and n is 0. In certain embodiments, m is 1, and nis 1.

In specific embodiments, m is 0, n is 1, and R^(5a) and R^(5b) are eachmethyl.

In certain embodiments, X is N In certain embodiments, X is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, X is CH.

In certain embodiments, Y is N In certain embodiments, Y is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, Y is CH.

In certain embodiments, Z is N In certain embodiments, Z is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, Z is CH.

In certain embodiments, X, Y, and Z are N. In certain embodiments, X andY are N, and Z is CH. In certain embodiments, X and Z are N, and Y isCH. In certain embodiments, Y and Z are N, and X is CH.

In certain embodiments, the compound provided herein is not4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazin-2-amine.In certain embodiments, the compound provided herein is not6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R)-3-(methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine.

In certain embodiments, when X, Y, and Z are N, and R^(5a) is hydrogen,R^(5b) is not heterocyclyl. In certain embodiments, when X, Y, and Z areN, and R^(5a) is hydrogen, R^(5b) is not 5-membered heterocyclyl. Incertain embodiments, when X, Y, and Z are and R^(5a) is hydrogen, R^(5b)is not pyrrolidinyl. In certain embodiments, when X, Y, and Z are N, andR^(5a) is hydrogen, R^(5b) is not pyrrolidin-1-yl.

In certain embodiments, when X and Z are N, Y is CH, and R^(5a) ishydrogen, R^(5b) is morpholino-substituted phenyl. In certainembodiments, when X and Z are N, Y is CH, and R^(5a) is hydrogen, R^(5b)is not 4-((R)-3-(methoxymethyl)morpholino)phenyl.

In one embodiment, provided herein is a compound selected from:

In one embodiment, the PI3K inhibitor is Compound I, or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In one embodiment, the PI3K inhibitor is Compound II, or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the PI3K inhibitor is Compound III,or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor isCompound IV, or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. In one embodiment, the PI3Kinhibitor is Compound V, or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the PI3K inhibitor is Compound VI, or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the PI3K inhibitor is Compound VII, or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In one embodiment, the PI3K inhibitor is Compound VIII, or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the PI3K inhibitor is Compound IX,or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor isCompound X, or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. In one embodiment, the PI3Kinhibitor is Compound XI, or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the PI3K inhibitor is Compound XII, or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the PI3K inhibitor is Compound XIII, or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In one embodiment the PI3K inhibitor is Compound XIV, or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the PI3K inhibitor is Compound XV,or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor isCompound XVI, or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

PD-1 and PD-L1 Inhibitors

Described herein are PI3K inhibitors in combination with PD-1 or PD-L1inhibitors.

The PD-1 (programmed cell death-1) receptor (also known as CD279) isexpressed on the surface of activated T cells. Its ligand, PD-L1, iscommonly expressed on the surface of dendritic cells or macrophages. Insome instances, PD1 and PD-L1 interaction halts or limits thedevelopment of the T cell response. When PD-L1 binds to PD-1, aninhibitory signal is transmitted into the T cell, which reduces cytokineproduction and suppresses T-cell proliferation. In some instances,cancer or tumor cells exploit this signaling pathway as a mechanism toevade detection and inhibit the immune response. In some instances,PD-L1 is overexpressed on cancer or tumor cells or on non-transformedcells in the tumor microenvironment. In some instances, PD-L1 expressedon the tumor cells binds to PD-1 receptors on the activated T cells,which leads to the inhibition of the cytotoxic T cells. Thesedeactivated T cells remain inhibited in the tumor microenvironment. ThePD1/PD-L1 pathway represents an adaptive immune resistance mechanismthat is exerted by cancer or tumor cells in response to endogenousanti-tumor activity.

PD-1 inhibitors (or anti-PD-1 agents) and PD-L1 inhibitors (oranti-PD-L1 agents) block the interaction between PD-1 and PD-L1 andboost the immune response against cancer cells. In some instances, theblockade of receptor engagement results in the amplification ofantigen-specific ‘T’ cell responses against cancer cells. In someinstances, antibodies that block the PD-1/PD-L1 interaction targetlymphocyte receptors or their ligands in order to enhance endogenousantitumor activity. In some instances, PD-1 inhibitors and PD-L1inhibitors overcome distinct immune suppressive pathways within thetumor microenvironment. In some instances, PD-1 inhibitors and/or PD-L1inhibitors are useful for treating cancer.

Any suitable PD-1 inhibitor or PD-L1 inhibitor may be used incombination with a PI3K inhibitor described herein. In some embodiments,the PD-1 inhibitor is an antagonist of PD-1. In some embodiments, thePD-L1 inhibitor is an antagonist of PD-L1. In some embodiments, the PD-1inhibitor or PD-L1 inhibitor is an antibody, variant, or biosimilarthereof. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is amonoclonal antibody. In some embodiments, the method of treating cancerwith a PI3K inhibitor described herein in combination with a PD-1 orPD-L1 inhibitor results in a transient reduction in the level ofsystemic immunosuppression.

Some embodiments provided herein describe a pharmaceutical compositionsor methods for use the pharmaceutical compositions comprising a PI3Kinhibitor described herein in combination with a PD-1 inhibitor. PD-1inhibitors for use in pharmaceutical compositions and methods providedherein include, but are not limited to, nivolumab (Opdivo®),pembrolizumab (Keytruda®), MEDI0680 (AMP-514), AMP-224,AMP-514(Amplimmune), BGB-A317, PDR001, REGN2810, JS001, AGEN2034, and variantsand biosimilars thereof. In some embodiments, the PD-1 inhibitor is tonivolumab (Opdivo®), pembrolizumab (Keytruda®), MEDI0680 (AMP-514),AMP-224, AMP-514 (Amplimmune), or variants or biosimilars thereof. Insome embodiments, the PD-1 inhibitor is pidilzumab (CT-011), or avariant or biosimilar thereof. In some embodiments, the PD-1 inhibitoris nivolumab (Opdivo®), or pembrolizumab (Keytruda®), or a variant orbiosimilar thereof. In some embodiments, the PD-1 inhibitor is nivolumab(Opdivo®), a nivolumab variant, or a nivolumab biosimilar. In someembodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®), apembrolizumab variant, or a pembrolizumab biosimilar. In someembodiments, the PD-1 inhibitor is BGB-A317, a BGB-A317 variant, or aBGB-A317 biosimilar. In some embodiments, the PD-1 inhibitor is PDR001,a PDR001 variant, or a PDR001 biosimilar. In some embodiments, the PD-1inhibitor is REGN2810, a REGN2810 variant, or a REGN2810 biosimilar.

Some embodiments provided herein describe pharmaceutical compositions ormethods for using the pharmaceutical compositions comprising a PI3Kinhibitor described herein in combination with a PD-L1 inhibitor. PD-L1inhibitors for use in pharmaceutical compositions and methods providedherein include but are not limited to Atezolizumab (Tecentriq® orMPDL3280A), avelumab (Bavencio®), Durvalumab (MEDI4736), MPDL3280A(RG7446), BMS-936559 (MDX-1105), MSB0010718C, YW243.55.S70, and variantsand biosimilars thereof. In some embodiments, the PD-L1 inhibitor isAtezolizumab (Tecentriq® or MPDL3280A), avelumab (Bavencio®), orDurvalumab (MEDI4736), or variants or biosimilars thereof. In someembodiments, the PD-L1 inhibitor is Atezolizumab (Tecentriq® orMPDL3280A) or avelumab (Bavencio®), or a variant or biosimilar thereof.In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq® orMPDL3280A), an atezolizumab variant, or an atezolizumab biosimilar. Insome embodiments, the PD-L1 inhibitor is avelumab (Bavencio®), avelumabvariant, or an avelumab biosimilar. In some embodiments, the PD-L1inhibitor is BMS-936559 (MDX-1105), BMS-936559 variant, or a BMS-936559biosimilar. In some embodiments, the PD-L1 inhibitor is durvalumab(MEDI4736), a durvalumab variant, or a durvalumab biosimilar.

In some embodiments, the compounds of Formula (I), or isotopic variants,pharmaceutically acceptable salts, solvates, hydrates, or prodrugsthereof, demonstrate higher avidity and biologic activity for a PI3K(e.g., PI3Kδ) compared to other PI3K inhibitors, including but notlimited to idelalisib. In some embodiments, the compounds of Formula(I), or isotopic variants, pharmaceutically acceptable salts, solvates,hydrates, or prodrugs thereof, demonstrate improved or superior drugdistribution to blood cells compared to other PI3K inhibitors, includingbut not limited to idelalisib.

In some embodiments, the combination therapy of a PD-1 or PD-L1inhibitor and a compound of Formula (I), or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,shows low toxicity to normal cells. In various embodiments, thecombination of a compound of Formula (I), or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,and a PD-1 or PD-L1 inhibitor is selectively toxic or more toxic torapidly proliferating cells, e.g., cancerous tumors, than to normalcells.

In some embodiments, the combination therapy described herein avoids orreduces adverse or unwanted, serious, or fatal side effects associatedwith the use of a PI3K inhibitor (e.g., idelalisib) and/or a PD-1 orPD-L1 inhibitor. In some embodiments, the combination therapy describedherein avoids, reduces, or minimizes (serious) infections, neutropenia,(severe) diarrhea, colon inflammation, colitis, lung tissue inflammation(pneumonitis), intestinal perforation, pneumonia, anemia,thrombocytopenia, nausea, fever, fatigue, cough, abdominal pain, chills,rash, vomiting, hypertriglyceridemia, hyperglycemia, elevated levels ofliver enzymes (e.g., ALT and ALST), liver toxicity, swelling inextremities, or a combination thereof in patients receiving thecombination therapy. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence ofinfection, including serious infection. In certain embodiments, thecombination therapy described herein avoids, reduces, or minimizes theincidence of neutropenia. In certain embodiments, the combinationtherapy described herein avoids, reduces, or minimizes the incidence ofdiarrhea, including severe diarrhea. In certain embodiments, thecombination therapy described herein avoids, reduces, or minimizes theincidence of colon inflammation. In certain embodiments, the combinationtherapy described herein avoids, reduces, or minimizes the incidence ofcolitis. In certain embodiments, the combination therapy describedherein avoids, reduces, or minimizes the incidence of lung tissueinflammation (pneumonitis). In certain embodiments, the combinationtherapy described herein avoids, reduces, or minimizes the incidence ofintestinal perforation. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence ofpneumonia. In certain embodiments, the combination therapy describedherein avoids, reduces, or minimizes the incidence of anemia. In certainembodiments, the combination therapy described herein avoids, reduces,or minimizes the incidence of thrombocytopenia. In certain embodiments,the combination therapy described herein avoids, reduces, or minimizesthe incidence of nausea. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence of fever.In certain embodiments, the combination therapy described herein avoids,reduces, or minimizes the incidence of fatigue. In certain embodiments,the combination therapy described herein avoids, reduces, or minimizesthe incidence of cough. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence ofabdominal pain. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence of chills.In certain embodiments, the combination therapy described herein avoids,reduces, or minimizes the incidence of rash. In certain embodiments, thecombination therapy described herein avoids, reduces, or minimizes theincidence of vomiting. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence ofhypertriglyceridemia.

In certain embodiments, the combination therapy described herein avoids,reduces, or minimizes the incidence of hyperglycemia. In certainembodiments, the combination therapy described herein avoids, reduces,or minimizes the incidence of elevated levels of liver enzymes (e.g.,ALT and ALST). In certain embodiments, the combination therapy describedherein avoids, reduces, or minimizes the incidence of liver toxicity. Incertain embodiments, the combination therapy described herein avoids,reduces, or minimizes the incidence of swelling in the extremities.

In some embodiments, the combination therapy described herein avoids orreduces adverse or unwanted side effects associated with chemotherapy,radiotherapy, or cancer therapy. In some instances, the combinationtherapies and/or compositions described herein provide chemo-protectiveand/or radio-protective properties to non-cancerous cells. In further oradditional embodiment, the lower amount/doses of PI3K inhibitor reducesor minimizes any undesired side-effects associated with chemotherapy.Non-limiting examples of side-effects associated with chemotherapy,radiotherapy, or cancer therapy include fatigue, anemia appetitechanges, bleeding problems, diarrhea, constipation, hair loss, nausea,vomiting, pain, peripheral neuropathy, swelling, skin and nail changes,urinary and bladder changes, and trouble swallowing.

Methods of Use

Some embodiments provided herein describe a method for treating orpreventing a proliferative disease or disorder comprising administeringa PI3K inhibitor in combination with a PD-1 inhibitor or a PD-L1inhibitor. In certain embodiments, provided herein are methods fortreating or preventing a disease comprising administering an effectiveamount of a compound of Formula (I), or an isotopic variant thereof or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand an effective amount of a PD-1 or PD-L1 inhibitor. In someembodiments, the compound of Formula (I) is Compound I or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is Compound IIor an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound III or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound IV or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is Compound Vor an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound VI or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound VII or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundVIII or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound IX or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound X or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is Compound XIor an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound XII or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound XIII or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundXIV or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound XV or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound XVI or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the PD-1 or PD-L1 inhibitor ispidilizumab, nivolumab, pembrolizumab, atezolizumab, avelumab,BMS-936559, BGB-A317, PDR001, REGN2810, or durvalumab. In otherembodiments, the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab,atezolizumab, BGB-A317, PDR001, REGN2810, or avelumab. In someembodiments, the PD-1 or PD-L1 inhibitor is pidilizumab, nivolumab,pembrolizumab, atezolizumab, avelumab, BMS-936559, or durvalumab. Inother embodiments, the PD-1 or PD-L1 inhibitor is nivolumab,pembrolizumab, atezolizumab, or avelumab.

In some embodiments, the proliferative disease is cancer. In certainembodiments, the proliferative disease is hematological cancer. Incertain embodiments, the proliferative disease is a cancer of thebreast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung,liver, larynx, oral cavity, colon and gastrointestinal tract (e.g.,esophagus, stomach, pancreas), brain, thyroid, blood, and lymphaticsystem.

In certain embodiments, the cancer treatable with the methods providedherein includes, but is not limited to, (1) leukemias, including, butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome or a symptom thereof (such as anemia, thrombocytopenia,neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RAwith ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB intransformation (RAEB-T), preleukemia, and chronic myelomonocyticleukemia (CMML), (2) chronic leukemias, including, but not limited to,chronic myelocytic (granulocytic) leukemia, chronic lymphocyticleukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas,including, but not limited to, Hodgkin's disease and non-Hodgkin'sdisease; (5) multiple myelomas, including, but not limited to,smoldering multiple myeloma, non-secretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenstrom's macroglobulinernia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease; (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, aligodendroghorna, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mutinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including, but not limited to, pheochromocytom andadrenocortical carcinoma; (14) thyroid cancer, including, but notlimited to, papillary or follicular thyroid cancer, medullary thyroidcancer, and anaplastic thyroid cancer; (15) pancreatic cancer,including, but not limited to, insulinoma, gastrinoma, glucagonoma,vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;(16) pituitary cancer, including, but limited to, Cushing's disease,prol actin-secreting tumor, acromegaly, and diabetes insipius; (17) eyecancer, including, but not limited, to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; (18) vaginal cancer, including, but not limited to,squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvarcancer, including, but not limited to, squamous cell carcinoma,melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget'sdisease; (20) cervical cancers, including, but not limited to, squamouscell carcinoma, and adenocarcinoma; (21) uterine cancer, including, butnot limited to, endometrial carcinoma and uterine sarcoma; (22) ovariancancer, including, but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; (23) esophagealcancer, including, but not limited to, squamous cancer, adenocarcinoma,adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamouscarcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oatcell (small cell) carcinoma; (24) stomach cancer, including, but notlimited to, adenocarcinoma, fungating (polypoid), ulcerating,superficial spreading, diffusely spreading, malignant lymphoma,liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26)rectal cancer; (27) liver cancer, including, but not limited to,hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer,including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas,including, but not limited to, pappillary, nodular, and diffuse; (30)lung cancer, including, but not limited to, non-small cell lung cancer,squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,large-cell carcinoma, and small-cell lung cancer; (31) testicularcancer, including, but not limited to, germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonserninoma, embryonalcarcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor);(32) prostate cancer, including, but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcorna; (33) penal cancer; (34) oralcancer, including, but not limited to, squamous cell carcinoma; (35)basal cancer; (36) salivary gland cancer, including, but not limited to,adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;(37) pharynx cancer, including, but not limited to, squamous cell cancerand verrucous; (38) skin cancer, including, but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma, andacral lentiginous melanoma; (39) kidney cancer, including, but notlimited to, renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer);(40) Wilms' tumor; (41) bladder cancer, including, but not limited to,transitional cell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; (42) reproductive cancers, such as cervical cancer,uterus cancer, ovarian cancer, or testicular cancer; (43) esophaguscancer; (44) laryngeal cancer; (45) head and neck cancer (such as mouth,nose, throat, larynx, sinuses, or salivary glands cancer); and othercancer, including, not limited to, myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma,synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, and papillary adenocarcinomas (SeeFishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co.,Philadelphia and Murphy et al., 1997, Informed Decisions: The CompleteBook of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin,Penguin Books U.S.A., Inc., United States of America). In someembodiments, the cancer is non-small cell lung cancer, melanoma, renalcell cancer, head and neck cancer, colon cancer, or mesothelioma. Insome embodiments, the cancer is non-small cell lung cancer. In someembodiments, the cancer is melanoma.

In certain embodiments, provided herein are methods of treating ahematological malignancy with a combination of an effective amount of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand an effective amount of PD-1 or PD-L1 inhibitor in a patient. Incertain embodiments, the hematological malignancy is a leukemia, alymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma,T-cell malignancy, or a B-cell malignancy. In some embodiments, thehematological malignancy is Hodgkin's lymphoma. In some embodiments, thehematological malignancy is chronic lymphocytic leukemia, follicularlymphoma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. Insome embodiments, the hematological malignancy is chronic lymphocyticleukemia or non-Hodgkin's lymphoma. In some embodiments, thehematological malignancy is chronic lymphocytic leukemia. In otherembodiments, the hematological malignancy is non-Hodgkin's lymphoma. Insome embodiments, the hematological malignancy is follicular lymphoma.In other embodiments, the hematological malignancy is diffuse largeB-cell lymphoma. In some embodiments, the compound of Formula (I) isCompound I or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. In some embodiments, the compoundof Formula (I) is Compound II or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound III or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is Compound IVor an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound V or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound VI or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundVII or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound VIII or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound IX or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is Compound Xor an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound XI or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound XII or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundXIII or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound XIV or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound XV or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundXVI or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

In certain embodiments, the hematological malignancy is a T-cellmalignancy. In certain embodiments, T-cell malignancies includeperipheral T-cell lymphoma not otherwise specified (PTCL-NOS),anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneousT-cell lymphoma, adult T cell leukemia/lymphoma (ATLL), blastic NK-celllymphoma, enteropathy-type T cell lymphoma, hematosplenic gamma-deltaT-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, ortreatment-related T-cell lymphomas.

In certain embodiments, the hematological malignancy is a B-cellmalignancy. In certain embodiments, B-cell malignancies include acutelymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), acute monocytic leukemia (AMoL), chroniclymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia(CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocyticlymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia,multiple myeloma, extranodal marginal zone B cell lymphoma, nodalmarginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt highgrade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL),immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, Bcell prolymphocytic leukemia, lymphoplastriacytic lymphoma, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal(thymic) large B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, or lymphomatoid granulomatosis. In certainembodiments, the B-cell malignancy is diffuse large B-cell lymphoma(DLBCL). In certain embodiments, the hematological malignancy is diffuselarge B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is anactivated B-cell DLBCL (ABC-DLBCL), a germinal center B-cell like DLBCL(GBC-DLBCL), a double hit DLBCL (DH-DLBCL), or a triple hit DLBCL(TH-DLBCL). In certain embodiments, the hematological malignancy isrelapsed-refractory diffuse large B-cell lymphoma (r/r DLBCL).

In certain embodiments, the hematological malignancy is a relapsed orrefractory hematological malignancy. In certain embodiments, therelapsed or refractory hematological malignancy is a relapsed orrefractory T-cell malignancy. In certain embodiments, the relapsed orrefractory hematological malignancy is a relapsed or refractory B-cellmalignancy.

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration as described elsewhere herein.

Dosages amid Dosing Regimens

In certain embodiments, the methods provided herein compriseadministering a compound of Formula (I), or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and a PD-1 or PD-L1 inhibitor to a patient simultaneously orsequentially by the same or different routes of administration.

The suitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. Recommendedroutes of administration for the second active agents are known to thoseof ordinary skill in the art. See, e.g. , Physicians' Desk Reference,1755-1760 (56th ed., 2002).

In certain embodiments, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and a PD-1 or PD-L1 inhibitor areadministered simultaneously, at essentially the same time, orsequentially. If administration takes place sequentially, the PD-1 orPD-L1 inhibitor may be administered before or after administration of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In some embodiments, the PD-1 or PD-L1 inhibitor is administered beforeadministration of a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In some embodiments, the PD-1 or PD-L1 inhibitor isadministered simultaneously with administration of a compound of Formula(I), an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. In some embodiments, the PD-1 orPD-L1 inhibitor is administered after the administration of a compoundof Formula (I), an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the PD-1 or PD-L1 inhibitor need not beadministered by means of the same vehicle. In some embodiments, the PD-1or PD-L1 inhibitor and a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof are administered in different vehicles. The PD-1 orPD-L1 inhibitor may be administered one or more times, and the number ofadministrations of each component of the combination may be the same ordifferent. In addition, a compound of Formula (I), or an isotopicvariant thereof, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the PD-1 or PD-L1 inhibitor need not beadministered at the same site.

In some instances, the methods described herein further compriseadministering the PI3K inhibitor in combination with PD-1 or PD-L1inhibitor to the subject or patient in need thereof in multiple cyclesrepeated on a regular schedule with periods of rest in between eachcycle. For example, in some instances, treatment is given for one weekfollowed by three weeks of rest is one treatment cycle.

In some instances, a cycle comprises administration of the PI3Kinhibitor at the same time as administration of the PD-1 or PD-L1inhibitor. In some instances, the PI3K inhibitor and the PD-1 or PD-L1inhibitor are administered for about 1 day, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 8 days,about 9 days, about 10 days, about 11 days, about 12 days, about 13days, about 14 days, about 15 days, about 16 days, about 17 days, about18 days, about 19 days, about 20 days, about 21 days, about 22 days,about 23 days, about 24 days, about 25 days, about 26 days, about 27days, or about 28 days.

In some instances, a cycle comprises administration of the PI3Kinhibitor first followed by administration of the PD-1 or PD-L1inhibitor second. In some instances, the PI3K inhibitor is administeredfor about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, or about 14 days followedby administration of the PD-1 or PD-L1 inhibitor for about 1 day, about2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, about 12days, about 13 days, or about 14 days.

In some instances, a cycle comprises administration of the PI3Kinhibitor first followed by concurrent administration of the PD-1 orPD-L1 inhibitor. In some instances, the PI3K inhibitor is firstadministered for about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, about 12 days, about 13 days, or about 14days followed by the concurrent administration of the PD-1 or PD-L1inhibitor for about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, about 12 days, about 13 days, or about 14days. In some instances, the PI3K inhibitor is first administered forabout 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, or about 7 days followed by the concurrent administrationof the PD-1 or PD-L1 inhibitor for about 1 day, about 2 days, about 3days, about 4 days, about 5 days, about 6 days, about 7 days, about 8days, about 9 days, about 10 days, about 11 days, about 12 days, about13 days, or about 14 days. In some instances, the PI3K inhibitor isfirst administered for about 7 days followed by the concurrentadministration of the PD-1 or PD-L1 inhibitor for about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 11 days, about 12days, about 13 days, or about 14 days. In some instances, the Pl3Kinhibitor is first administered for about 7 days followed by theconcurrent administration of the PD-1 or PD-L1 inhibitor for about 10days, about 11 days, about 12 days, about 13 days, or about 14 days.

In some instances, a cycle comprises administration of the PI3Kinhibitor only. In some instances, the PI3K inhibitor is administeredfor about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, about 14 days, about 15days, about 16 days, about 17 days, about 18 days, about 19 days, about20 days, about 21 days, about 22 days, about 23 days, about 24 days,about 25 days, about 26 days, about 27 days, or about 28 days.

In some instances, a cycle comprises administration of the PD-1 or PD-L1inhibitor only. In some instances, the PD-1 or PD-L1 inhibitor isadministered for about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, about 12 days, about 13 days, about 14days, about 15 days, about 16 days, about 17 days, about 18 days, about19 days, about 20 days, about 21 days, about 22 days, about 23 days,about 24 days, about 25 days, about 26 days, about 27 days, or about 28days.

In some instances, the method for multiple cycle chemotherapy comprisesthe administration of a second cycle within about 60 days or about 3months. In some instances, the method for multiple cycle chemotherapycomprises the administration of a second cycle within 50 days. Inanother instance, the second cycle is administered within 45, 40, 35,30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day(s) of thefirst cycle. In some embodiments, the administration of any additionalcycles is within 50 days of the previous cycle. In some embodiments, theadministration of any additional cycles is within 10 days of theprevious cycle. In some embodiments, the administration of anyadditional cycles is within 9 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 8days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 7 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 6days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 5 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 4days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 3 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 2days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 1 day of the previous cycle. In anotherembodiment, the additional cycle is administered within 45, 40, 35, 30,25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days of theprevious cycle.

The length of a treatment cycle depends on the treatment being given. Insome embodiments, the length of a treatment cycle ranges from two to sixweeks. In some embodiments, the length of a treatment cycle ranges fromfour to six weeks. In some embodiments, the length of a treatment cycleis 28 days. In some embodiments, the length of a treatment cycle is 56days. In some embodiments, a treatment cycle lasts one, two, three, orfour weeks. In some embodiments, a treatment cycle lasts four weeks. Thenumber of treatment doses scheduled within each cycle also variesdepending on the drugs being given.

In some instances, the method for the administration of multiplecompounds comprises administering compounds within 48 hours or less ofeach other. In some embodiments administration occurs within 24 hours,12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances,the compounds are administered simultaneously. One example ofsimultaneous administration is the injection of one compound immediatelybefore, after, or during the oral administration of the second compound,immediately referring to a time less than about 5 minutes.

In some instances, the method for the administration of multiplecompounds occurs in a sequential order, wherein the PI3K inhibitor isadministered before the PD-1 or PD-L1 inhibitor. In another instance,the PD-1 or PD-L1 inhibitor is administered before the PI3K inhibitor.

In some instances, the method for administering the PI3K inhibitor isoral and the method for administering the PD-1 or PD-L1 inhibitor is byinjection. In some instances, the method for administering the PI3Kinhibitor is by inhalation and the method for administering the PD-1 orPD-L1 inhibitor is by injection. In some instances, the method foradministering the PI3K inhibitor is by injection and the method foradministering the PD-1 or PD-L1 inhibitor is by injection.

In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and a PD-1 or PD-L1 inhibitor are cyclicallyadministered to a patient. As discussed above, cycling therapy involvesthe administration of an active agent or a combination of active agentsfor a period of time, followed by a rest for a period of time, andrepeating this sequential administration. In some embodiments, cyclingtherapy reduces the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improves the efficacy of the treatment.

In some embodiments, the compound of Formula (I) is administered daily,every other day, every other day 3 times a week, every 2 weeks, every 3weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5times a week, 6 times a week, once a month, twice a month, 3 times amonth, once every 2 months, once every 3 months, once every 4 months,once every 5 months, or once every 6 months. In some embodiments, thecompound of Formula (I) is administered daily.

In some embodiments, the PD-1 or PD-L1 inhibitor is administered daily,every other day, every other day 3 times a week, every 3 days, every 4days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks,every 4 weeks, every 5 weeks, bi-weekly, 3 times a week, 4 times a week,5 times a week, 6 times a week, once a month, twice a month, 3 times amonth, once every 2 months, once every 3 months, once every 4 months,once every 5 months, or once every 6 months.

In some instances, the compound of Formula (I) or the PD-1 or PD-L1inhibitor is optionally given continuously; alternatively, the dose ofdrug being administered is temporarily reduced or temporarily suspendedfor a certain length of time (i.e., a “drug holiday”). In someembodiments, the length of the drug holiday varies between 2 days and 1year, including by way of example only, 2 days, 3 days, 4 days, 5 days,6 days, 7 days, 8 days, 9 days,10 days, 12 days, 14 days, 15 days, 20days, 21 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days,150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days,350 days, or 365 days. The dose reduction during a drug holiday includesfrom 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%.

In certain embodiments, in the treatment, prevention, or amelioration ofone or more symptoms of the disorders, diseases, or conditions describedherein, an appropriate dosage level of a compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof generally is ranging from about 1to about 1000 mg, from about 1 to about 500 mg, from about 5 to about500 mg, from about 5 to about 200 mg, from about 5 to about 250 mg orfrom about 10 to about 150 mg which can be administered in single ormultiple doses. In certain embodiments, the compound of Formula (I), oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155,160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325,350, 375, 400, 450 or 500 mg. In certain embodiments, the compound ofFormula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof is administered inan amount of about 1, about 5, about 10, about 15, about 20, about 25,about 30, about 35, about 40, about 45, about 50, about 55, about 60,about 65, about 70, about 75, about 80, about 85, about 90, about 95,about 100, about 105, about 110, about 115, about 120, about 125, about130, about 135, about 140, about 145, about 150, about 155, about 160,about 165, about 170, about 175, about 180, about 185, about 190, about195, about 200, about 225, about 250, about 275, about 300, about 325,about 350, about 375, about 400, about 450, or about 500 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 30 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 45 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 60 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 90 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 120 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 150 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 180 mg. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 1, 5, 10, 15, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105,110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175,180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450 or500 mg/day. In certain embodiments, the compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 30 mg/day. In certain embodiments, the compound of Formula (I), oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 45 mg/day. In certain embodiments, the compound of Formula (I), oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 60 mg/day. In certain embodiments, the compound of Formula (I), oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 90/day mg. In certain embodiments, the compound of Formula (I), oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 120/day mg. In certain embodiments, the compound of Formula (I),or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 150/day mg. In certain embodiments, the compound of Formula (I),or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 180/day mg.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets or capsules containing fromabout 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, in one embodiment, about 1, about 5, about10, about 15, about 20, about 25, about 50, about 75, about 100, about150, about 200, about 250, about 300, about 400, about 500, about 600,about 750, about 800, about 900, and about 1,000 mg of the compound ofFormula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof for thesymptomatic adjustment of the dosage to the patient to be treated. Insome embodiments, the pharmaceutical compositions provided herein can beformulated in the form of tablets containing about 60 mg of a compoundof Formula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. Thepharmaceutical compositions can be administered on a regimen of 1 to 4times per day, including once, twice, three times, and four times perday. In some embodiments, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered once per day. In someembodiments, about 30 mg, about 45 mg, or about 60 mg of the compound ofFormula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof is administeredonce per day. In some embodiments, the compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered to a patient inneed thereof in an amount of about 60 mg daily for 28 days or 56 days.In certain specific embodiments, a compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered to a patient inneed thereof in an amount of about 60 mg daily for 28 days. In otherspecific embodiments, a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 60 mg daily for 56 days.

In the methods of treatment, prevention, or amelioration of one or moresymptoms of the disorders, diseases, or conditions described herein, anappropriate dosage level of a PD-1 or PD-L1 inhibitor generally isranging from about 0.1 to 2000 mg per day. In some embodiments, 1-500 mgonce or multiple times per day is effective to obtain the desiredresults.

In certain embodiments, the PD-1 or PD-L1 inhibitor is pidilizumab andthe amount of pidilizumab that is administered is from about 10 mg/dayup to, and including, 1000 mg/day. In certain embodiments, the amount ofpidilizumab that is administered is from about 10 mg/day to 600 mg/day.In certain embodiments, the amount of pidilizumab that is administeredis from about 100 mg/day to 600 mg/day. In certain embodiments, theamount of pidilizumab that is administered per day is about 10 mg, about50 mg, about 100 mg, about 120 mg, about 240 mg, about 420 mg or about560 mg,

In certain embodiments, the methods described herein further compriseadministering pidilizumab intravenously at a dosage of 1-10 mg/kg eachweek. In certain embodiments, pidilizumab is administered intravenouslyat a dosage of 3 mg/kg each week. In another embodiment, pidilizumab isadministered intravenously at a dosage of about 100 mg, about 150 mg,about 240 mg, about 360 mg or about 450 mg each week.

In certain embodiments, the PD-1 or PD-L1 inhibitor is nivolumab and theamount of nivolumab that is administered is from about 10 mg/day up to,and including, 1000 mg/day. In certain embodiments, the amount ofnivolumab that is administered is from about 10 mg/day to 600 mg/day. Incertain embodiments, the amount of nivolumab that is administered isfrom about 100 mg/day to 600 mg/day. In certain embodiments, the amountof nivolumab that is administered per day is about 10 mg, about 60 mg,about 120 mg, about 180 mg, about 240 mg, about 420 mg or about 560 mg.

In certain embodiments, the methods described herein further compriseadministering nivolumab intravenously at a dosage of 1-10 mg/kg everytwo weeks. In certain embodiments, nivolumab is administeredintravenously at a dosage of 3 mg/kg every two weeks. In certainembodiments, 3 mg/kg of nivolumab is administered as an intravenousinfusion over 60 minutes every two weeks. In another embodiment, theamount of nivolumab that is administered is about 100 mg, about 150 mg,about 240 mg, about 360 mg or about 450 mg every two weeks.

In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab andthe amount of pembrolizumab that is administered is from about 10 mg/dayup to, and including, 1000 mg/day. In certain embodiments, the amount ofpembrolizumab that is administered is from about 10 mg/day to 600mg/day. In certain embodiments, the amount of pembrolizumab that isadministered is from about 100 mg/day to 600 mg/day. In certainembodiments, the amount of pembrolizumab that is administered per day isabout 10 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg,about 420 mg or about 560 mg.

In certain embodiments, the methods described herein further compriseadministering pembrolizumab intravenously at a dosage of 1-10 mg/kgevery three weeks. In certain embodiments, pembrolizumab is administeredintravenously at a dosage of 2 mg/kg every three weeks. In certainembodiments, 2 mg/kg of pembrolizumab is administered as an intravenousinfusion over 30 minutes every three weeks. In another embodiment, theamount of pembrolizumab that is administered is about 50 mg, about 100mg, about 200 mg, about 300 mg or about 400 mg every three weeks.

In certain embodiments, the PD-1 or PD-L1 inhibitor is BGB-A317 andBGB-A317 is administered to a subject in need thereof with doses rangingfrom 0.5 to 10 mg/kg. In some embodiments, BGB-A317 is administered at adosage of about 2 mg/kg or about 5 mg/kg. In some embodiments, BGB-A317is administered at a dosage of about 2 mg/kg. In some embodiments,BGB-A317 is administered at a dosage of about 5 mg/kg.

In certain embodiments, the PD-1 or PD-L1 inhibitor is BGB-A317 andBGB-A317 is administered to a subject in need thereof with biweeklyintravenous doses ranging from 0.5 to 10 mg/kg. In some embodiments,BGB-A317 is administered biweekly at a dosage of about 2 mg/kg or about5 mg/kg. In some embodiments, BGB-A317 is administered biweekly at adosage of about 2 mg/kg. In some embodiments, BGB-A317 is administeredbiweekly at a dosage of about 5 mg/kg. In some embodiments, BGB-A317 isadministered biweekly at a dosage of about 2 mg/kg or about 5 mg/kgintravenously.

In some embodiments, BGB-A317 is administered intravenously once everythree weeks at a dose ranging from about 0.5 to 10 mg/kg. In someembodiments, BGB-A317 is administered once every three weeks at a dosageof about 2 mg/kg or about 5 mg/kg. In some embodiments, BGB-A317 isadministered once every three weeks at a dosage of about 2 mg/kg. Insome embodiments, BGB-A317 is administered once every three weeks at adosage of about 5 mg/kg. In some embodiments, BGB-A317 is administeredonce every three weeks at a dosage of about 2 mg/kg or about 5 mg/kgintravenously.

In some embodiments, BGB-A317 is administered to the subject in needthereof in an amount of about 200 mg or 300 mg. In some embodiments,BGB-A317 is administered to the subject in need thereof in an amount ofabout 200 mg once every two weeks. In some embodiments, BGB-A317 isadministered to the subject in need thereof in an amount of about 300 mgonce every two weeks. In some embodiments, BGB-A317 is administered tothe subject in need thereof in an amount of about 200 mg once everythree weeks. In some embodiments, BGB-A317 is administered to thesubject in need thereof in an amount of about 300 mg once every threeweeks.

In some embodiments, the PD-1 or PD-L1 inhibitor is PDR001 and PDR001 isadministered to a subject in need thereof via intravenous infusion over30 mins. In other embodiments, PDR001 is administered to a subject inneed thereof via intravenous infusion for up to 2 hours. In someembodiments, PDR001 is administered to a subject in need thereof onceevery 4 or 8 weeks. In certain embodiments, PDR001 is administered to asubject in need thereof once every 4 weeks. In other embodiments, PDR001is administered to a subject in need thereof once every 8 weeks.

In some embodiments, the PD-1 or PD-L1 inhibitor is REGN2810 andREGN2810 is administered to a subject in need thereof intravenouslyevery 2 weeks. In some embodiments, REGN2810 is administered to asubject in need thereof in an amount of about 200 mg. In someembodiments, REGN2810 is administered to a subject in need thereof in anamount of about 3 mg/kg. In other embodiments, REGN2810 is administeredto a subject in need thereof in an amount of about 1 mg/kg. In someembodiments, REGN2810 is administered to a subject in need thereof in anamount of about 200 mg once every two weeks. In some embodiments,REGN2810 is administered to a subject in need thereof in an amount ofabout 3 mg/kg once every two weeks. In other embodiments, REGN2810 isadministered to a subject in need thereof in an amount of about 1 mg/kgonce every two weeks.

In certain embodiments, the PD-1 or PD-L1 inhibitor is atezolizumab andthe amount of atezolizumab that is administered is from about 10 mg/dayup to, and including, 1200 mg/day. In certain embodiments, the amount ofatezolizumab that is administered is from about 10 mg/day to 600 mg/day.In certain embodiments, the amount of atezolizumab that is administeredis from about 100 mg/day to 600 mg/day. In certain embodiments, theamount of atezolizumab that is administered per day is about 10 mg,about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 420 mg orabout 560 mg.

In certain embodiments, the methods described herein further compriseadministering atezolizumab at a dosage of 1200 mg/20 mL in a singledose. In certain embodiments, atezolizumab is administered at a dosageof 15 mg/kg in a single dose. In some embodiments, atezolizumab isadministered at a dosage of 1200 mg as an intravenous infusion. In someembodiments, atezolizumab is administered at a dosage of 1200 mg as anintravenous infusion every 3 weeks. In some embodiments, atezolizumab isadministered at a dosage of 1200 mg as an intravenous infusion over 60minutes every 3 weeks. In another embodiment, the amount of atezolizumabthat is administered is about 600 mg, about 900 mg, about 1000 mg, about1100 mg, about 1200 mg, about 1300 mg, about 1500 mg, or about 1800 mgin a single dose.

In certain embodiments, the PD-1 or PD-L1 inhibitor is avelumab and theamount of avelumab that is administered is from about 10 mg/day up to,and including, 1000 mg/day. In certain embodiments, the amount ofavelumab that is administered is from about 10 mg/day to 600 mg/day. Incertain embodiments, the amount of avelumab that is administered is fromabout 100 mg/day to 600 mg/day. In certain embodiments, the amount ofavelumab that is administered per day is about 10 mg, about 50 mg, about100 mg, about 300 mg, about 500 mg, about 700 mg or about 900 mg.

In certain embodiments, the methods described herein further compriseadministering avelumab at a dosage of 10 mg/kg every two weeks. In someembodiments, 10 mg/kg of avelumab is administered as an intravenousinfusion every two weeks. In some embodiments, 10 mg/kg of avelumab isadministered as an intravenous infusion over 60 minutes every two weeks.In certain embodiments, avelumab is administered at a dosage of 20 mg/kgevery two weeks. In another embodiment, the amount of avelumab that isadministered is about 100 mg, 300 mg, 500 mg, 750 mg, 1200 mg or 1500 mgin a every two weeks. In some instances, the patient is premedicatedwith acetaminophen and/or an antihistamine for the first 4 infusions andsubsequently as needed.

In certain embodiments, the PD-1 or PD-L1 inhibitor is BMS-936559 andthe amount of BMS-936559 that is administered is from about 10 mg/day upto, and including, 1000 mg/day. In certain embodiments, the amount ofBMS-936559 that is administered is from about 10 mg/day to 600 mg/day.In certain embodiments, the amount of BMS-936559 that is administered isfrom about 100 mg/day to 600 mg/day. In certain embodiments, the amountof BMS-936559 that is administered per day is about 10 mg, about 30 mg,about 80 mg, about 100 mg, about 200 mg, about 300 mg or about 500 mg.

In certain embodiments, the PD-1 or PD-L1 inhibitor is BMS-936559 andthe amount of BMS-936559 that is administered is 3 mg/kg every twoweeks. In certain embodiments, the amount of BMS-936559 that isadministered is 2 mg/kg every two weeks. In another embodiment, theamount of BMS-936559 that is administered is about 50 mg, 100 mg, 100mg, 250 mg, 350 mg or 500 mg every two weeks.

In certain embodiments, the PD-1 or PD-L1 inhibitor is durvalumab andthe amount of durvalumab that is administered is from about 10 mg/day upto, and including, 1000 mg/day. In certain embodiments, the amount ofdurvalumab that is administered is from about 1.0 mg/day to 600 mg/day.In certain embodiments, the amount of durvalumab that is administered isfrom about 100 mg/day to 600 mg/day. In certain embodiments, the amountof durvalumab that is administered per day is about 10 mg, about 50 mg,about 100 mg, about 300 mg, about 500 mg, about 700 mg or about 900 mg.

In certain embodiments, the PD-1 or PD-L1 inhibitor is durvalumab andthe amount of durvalumab that is administered is 10 mg/kg every twoweeks. In certain embodiments, the amount of durvalumab that isadministered is 20 mg/kg every four weeks. In another embodiment, theamount of durvalumab that is administered is about 100 mg, 400 mg, 800mg, 1200 mg, 1500 mg or 2000 mg in a single dose.

In certain embodiments, a PD-1 or PD-L1 inhibitor is administered onceper day, twice per day, or three times per day. In certain embodiments,the PD-1 or PD-L1 inhibitor is administered once per day. In certainembodiments, the PD-1 or PD-L1 inhibitor is administered once per day,twice per day, or three times per day. In certain embodiments, the PD-1or PD-L1 inhibitor is administered once per day. In certain embodiments,the PD-1 or PD-L1 inhibitor is co-administered (e.g., in a single dosageform), once per day.

In certain embodiments, the PD-1 or PD-L1 inhibitor is administered oncea week. In certain embodiments, the PD-1 or PD-L1 inhibitor isadministered once every two, three, four or five weeks. In certainembodiments, the PD-1 or PD-L1 inhibitor is administered intravenouslyor through direct injection. In certain embodiments of the combinationtherapy described herein, one agent is administered orally and anotheragent is administered intravenously.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Additional Combination Therapy

In certain embodiments, the methods of combination therapy comprising acompound of Formula (I), an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a PD-1 or PD-L1 inhibitor can also be combined or used incombination with a third agent or therapies useful in the treatment,prevention, or amelioration of one or more symptoms of a proliferativedisorders, diseases, or conditions.

Suitable third agent of therapies include, but are not limited to, (1)alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and xirnelagatran, (7) anti-diabetic agents, such asbiguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose),insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g.,glimepiride, glyburide, and glipizide), thiozolidinediones (e.g.,troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma monists;(8) antifungal agents, such as amorolfine, amphotericin B,anidulafungin, bifonazole, butenafine, butoconazole, caspofungin,ciclopirox, clotrimazole, econazole, fenticonazole, filipin,fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole,posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine,terconazole, tioconazole, and voriconazole; (9) antiinflammatories,e.g., non-steroidal anti-inflammatory agents, such as aceclofenac,acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac,carprofen, celecoxib, choline magnesium salicylate, diclofenac,diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen,flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lomoxicam,loxoprolen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam,metamizole, methyl salicylate, magnesium salicylate, nabumetone,naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone,piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen,tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such asfolate antagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid secjuestrants, such as questran; (17) calcium channelblockers, such as amlodipine besylate; (18) chemotherapeutic agents;(19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib androfecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as azathioprineand cyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat, and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

In certain embodiments, the third therapies that may be used incombination with the methods provided herein include, but are notlimited to, surgery, endocrine therapy, biologic response modifiers(e.g., interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, and agents to attenuate any adverseeffects (e.g., antiemetics).

In certain embodiments, the third therapeutic agents that may be used incombination with the compounds provided herein include, but are notlimited to, alkylating drugs (mechlorethamine, chlorambucil,cyclophosphamide, melphalan, and ifosfamide), antimetabolites(cytarabine (also known as cytosine arabinoside or Ara-C), andmethotrexate), purine antagonists and pyrimidine antagonists(6-mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindlepoisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins(etoposide, irinotecan, and topotecan), antibiotics (daunorubicin,doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine andlomustine), enzymes (asparaginasc), and hormones (tamoxifen, leuprolide,flutamide, and megestrol), imatinib, adriamycin, dexamethasone, andcyclophosphamide. For a more comprehensive discussion of updated cancertherapies; See, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://www.fda.gov/cder/cancer/dniglistframe.htm, andThe Merck Manual, Seventeenth Ed, 1999, the entire contents of which arehereby incorporated by reference.

In another embodiment, methods provided herein comprise administrationof a compound of Formula (I), or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a PD-1 or PD-L1 inhibitor, together with administration of one ormore chemotherapeutic agents and/or therapies selected from: alkylationagents (e.g., cisplatin, carboplatin); antimetabolites (e.g.,methotrexate and 5-FU); antitumor antibiotics (e.g., adriamymycin andbleomycin); antitumor vegetable alkaloids (e.g., taxol and etoposide);antitumor hormones (e.g., dexamethasone and tamoxifen); antitumorimmunological agents (e.g., interferon α, β, and γ); radiation therapy;and surgery. In certain embodiments, the one or more chemotherapeuticagents and/or therapies are administered to the subject before, during,or after the administration of a compound of Formula (I), or an isotopicvariant thereof, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and a PD-1 or PD-L1 inhibitor.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a PD-1 or PD-L1 inhibitor. When a compound of Formula (I) and a PD-1or PD-L1 inhibitor are used contemporaneously with one or more otherdrugs, a pharmaceutical composition containing such other drugs inaddition to the compound of Formula (I), or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and a PD-1 or PD-L1 inhibitor can be utilized, but is notrequired. Accordingly, the pharmaceutical compositions provided hereininclude those that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound of Formula (I).

Pharmaceutical Compositions and Routes of Administration

Provided herein is a pharmaceutical composition comprising a compound ofFormula (I), a PD-1 or PD-L1 inhibitor, and a pharmaceuticallyacceptable excipient, adjuvant, carrier, buffer, or stabilizer. In someembodiments, the compound of Formula (I) and a PD-1 or PD-L1 inhibitorare present in the same pharmaceutical composition. In some embodiments,the compound of Formula (I) and the PD-1 or PD-L1 inhibitor are indifferent pharmaceutical compositions.

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, and one or more pharmaceutically acceptable excipients orcarriers. The pharmaceutical compositions provided herein that areformulated for oral administration may be in tablet, capsule, powder, orliquid form. In some embodiments, a tablet comprises a solid carrier oran adjuvant. Liquid pharmaceutical compositions generally comprise aliquid carrier such as water, petroleum, animal or vegetable oils,mineral oil, or synthetic oil. Physiological saline solution, dextroseor other saccharide solution, or glycols such as ethylene glycol,propylene glycol, or polyethylene glycol may be included. In someembodiments, a capsule comprises a solid carrier such as gelatin.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers. Where pharmaceutical compositions may be formulated forintravenous, cutaneous or subcutaneous injection, the active ingredientwill be in the form of a parenterally acceptable aqueous solution, whichis pyrogen-free and has a suitable pH, isotonicity, and stability. Thoseof relevant skill in the art are well able to prepare suitable solutionsusing, for example, isotonic vehicles, such as Sodium Chlorideinjection, Ringer's injection, or Lactated Ringer's injection. In someembodiments, preservatives, stabilizers, buffers, antioxidants, and/orother additives are included as required.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

The pharmaceutical compositions can also be formulated as modifiedrelease dosage forms, including delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, andprogrammed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology.2nd Edition, Rathbone et at. , Eds., Marcel Dekker, Inc.: New York,N.Y., 2008).

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

In certain embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more chemotherapeutic agents as defined herein.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl-and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungi static concentrations. All parenteral formulations must besterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized, nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand metliacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl] rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. In some embodiments, the emulsifier in a cream formulation isa nonionic, anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOLE®, hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinyl alcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,anchor stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein, and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate), polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate, degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethylmethacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, poly vinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al. J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinformulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet-and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,04,534, 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Articles of Manufacture

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes one or more containers and a dosage form of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a PD-1 or PD-L1 inhibitor.

In certain embodiments, the kit provided herein includes one or morecontainers and a dosage form of a compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and PD-1 or PD-L1 inhibitor. Kitsprovided herein can further include devices that are used to administerthe active ingredients. Examples of such devices include, but are notlimited to, syringes, needle-less injectors drip bags, patches, andinhalers.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

Additional Embodiments

Embodiments include embodiment P1 to P31 following.

Embodiment P1. A method for treating or preventing a disease comprisingadministering:

(i) an effective amount of a compound of Formula (I);

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   -   X, Y, and Z are each independently N or CR^(X), with the proviso        that at least two of X, Y, and Z are nitrogen atoms; where R^(X)        is hydrogen or C₁₋₆ alkyl;    -   R¹ and R² are each independently (a) hydrogen, cyano, halo, or        nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b), R^(1c), and        R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅        aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c)        together with the N atom to which they are attached form        heterocyclyl;    -   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³        and R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆        heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;    -   R^(5a) (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,        heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OCC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or        —(CR^(5f)R^(5g))_(n)-heteroaryl;    -   R^(5d) and R^(5e) are each independently (a) hydrogen or        halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   R^(5f) and R^(5g) are each independently (a) hydrogen or        halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyl, C₃₋₁₀        cycloalkyl. C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c); or        —S(O)₂NR^(1b)R^(1c); or (d) when one occurrence of R^(5f) and        one occurrence of R^(5g) are attached to the same carbon atom,        the R^(5f) and R^(5g) together with the carbon atom to which        they are attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;    -   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or        —SO₂—C₁₋₆ alkyl;    -   m is 0 or 1; and    -   n is 0, 1, 2, 3, or 4;    -   wherein each alkyl, alkylene, heteroalkylene, alkenyl,        alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,        aralkyl, heteroaryl, and heterocyclyl in R¹, R², R³, R⁴, R⁶,        R^(X), R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), R^(5c),        R^(5d), R^(5e), R^(5f), and R^(5g) is optionally substituted        with one, two, three, four, or five substituents Q, wherein each        substituent Q is independently selected from (a) oxo, cyano,        halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and        heterocyclyl, each of which is further optionally substituted        with one, two, three, or four substituents Q^(a); and (c)        —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),        —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),        —OC(O)NR^(1b)R^(1c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),        —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),        —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),        —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),        —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),        —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c),        and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and        R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅        aralkyl, heteroaryl, or heterocyclyl, each of which is further        optionally substituted with one, two, three, or four        substituents Q^(a); or (iii) R^(b) and R^(c) together with the N        atom to which they are attached form heterocyclyl, which is        further optionally substituted with one, two, three, or four        substituents Q^(a);    -   wherein each Q^(a) is independently selected from the group        consisting of (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅        aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),        —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),        —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),        —OC(═NR^(e))NR^(f)R^(g), —OS(O)NR^(f)R^(g),        —NR^(e)C(═NR^(h))NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),        —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),        —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),        —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),        —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),        —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e),        R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,        C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and        R^(g) together with the N atom to which they are attached form        heterocyclyl; or    -   wherein two substituents Q that are adjacent to each other        optionally form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or        heterocyclyl, each optionally substituted with one, two, three,        or four substituents Q^(a); and

(ii) an effective amount of a PD-1 or PD-L1 inhibitor, wherein thedisease is cancer.

Embodiment P2. The method of embodiment P1, wherein R^(5b) is (a) halo;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

Embodiment P3. The method of embodiment P1, wherein R^(5a) and R^(5b)are each independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

Embodiment P4. The method of embodiment P3, wherein R^(5a) and R^(5b)are each methyl, optionally substituted with one, two, or three halo(s).

Embodiment P5. The method of any one of embodiments P1-P4, wherein n is1.

Embodiment P6. The method of any one of embodiments P1-P5, whereinR^(5f) and R^(5g) are each hydrogen.

Embodiment P7. The method of any one of embodiments P1-P4, wherein n is0.

Embodiment P8. The method of any one of embodiments P1-P7, wherein m is0.

Embodiment P9. The method of any one of embodiments P1-P8, wherein thecompound of Formula (I) is of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one, two, three, or foursubstituents Q^(a).

Embodiment P10. The method of any one of embodiments P1-P9, wherein thecompound of Formula (I) is Compound I:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment P11. The method of any one of embodiments P1-P10, wherein thePD-1 or PD-L1 inhibitor is pidilizumab, nivolumab, pembrolizumab,atezolizumab, avelumab, BMS-936559, BGB-A317, PDR001, REGN2810, ordurvalumab, or a variant or biosimilar thereof, or combinations thereof.

Embodiment P12. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is pidilizumab, or a variant or biosimilar thereof.

Embodiment P13. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is nivolumab, or a variant or biosimilar thereof.

Embodiment P14. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is pembrolizumab, or a variant or biosimilar thereof.

Embodiment P15. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is atezolizumab, or a variant or biosimilar thereof.

Embodiment P16. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is BMS-936559, or a variant or biosimilar thereof.

Embodiment P17. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is durvalumab, or a variant or biosimilar thereof.

Embodiment P18. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is BGB-A317, or a variant or biosimilar thereof.

Embodiment P19. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is PDR001, or a variant or biosimilar thereof.

Embodiment P20. The method of embodiment P11, wherein the PD-1 or PD-L1inhibitor is REGN2810, or a variant or biosimilar thereof.

Embodiment P21. The method of any one of embodiments P1-P20, wherein thecancer is non-Hodgkin's lymphoma, non-small cell lung cancer, melanoma,renal cell cancer, head and neck cancer, colon cancer, or mesothelioma.

Embodiment P22. The method of any one of embodiments P1-P21, wherein thecancer is melanoma.

Embodiment P23. The method of any one of embodiments P1-P22, wherein theadministration of compounds occurs in one or more cycles.

Embodiment P24. A method for multiple cycle chemotherapy in a subject,wherein the method comprises administering to the subject at least twochemotherapy cycles, wherein in each chemotherapy cycle, a PI3Kinhibitor and a PD-1 or PD-L1 inhibitor is administered to the subject.

Embodiment P25. The method of embodiment 24, wherein the compounds areadministered within 6 hours or less of each other.

Embodiment P26. The method of either of embodiments P24 or P25, whereinthe compounds are administered within 1 hour or less of each other.

Embodiment P27. The method of any one of embodiments P24-P26, whereinthe compounds are administered simultaneously.

Embodiment P28. The method of any one of embodiments P24-P26, whereinthe compounds are administered sequentially.

Embodiment P29. The method of any one of embodiments P24-P28, whereinthe PI3K inhibitor is administered orally and the PD-1 or PD-L1inhibitor is administered by injection.

Embodiment P30. The method of any one of embodiments P24-P29, whereinthe administration of the second cycle is within 50 days.

Embodiment P31. The method of any one of embodiments P24-P29, whereinthe administration of any additional cycle is within 50 days of theprevious cycle.

Further embodiments include embodiments 1 to 42 following.

Embodiment 1. A method for treating or preventing cancer, comprisingadministering:

(i) an effective amount of a compound of Formula (I);

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   -   X, Y, and Z are each independently N or CR^(X), with the proviso        that at least two of X, Y, and Z are nitrogen atoms; where R^(X)        is hydrogen or C₁₋₆ alkyl;    -   R¹ and R² are each independently (a) hydrogen, cyano, halo, or        nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —C(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b), R^(1c), and        R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅        aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c)        together with the N atom to which they are attached form        heterocyclyl;    -   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³        and R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆        heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;    -   R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,        heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1d))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1d))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1a)R^(1c), —NR^(1a)C(═NR¹d)NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or        —(CR^(5f)R^(5g))_(n)-heteroaryl;    -   R^(5d) and R^(5e) are each independently (a) hydrogen or        halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a); —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   R^(5f) and R^(5g) are each independently (a) hydrogen or        halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c); or        —S(O)₂NR^(1b)R^(1c); or (d) when one occurrence of R^(5f) and        one occurrence of R^(5g) are attached to the same carbon atom,        the R^(5f) and R^(5g) together with the carbon atom to which        they are attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;    -   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or        —SO₂—C₁₋₆ alkyl;    -   m is 0 or 1; and    -   n is 0, 1, 2, 3, or 4;    -   wherein each alkyl, alkylene, heteroalkylene, alkenyl,        alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,        aralkyl, heteroaryl, and heterocyclyl in R¹, R², R³, R⁴, R⁶,        R^(X), R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), R^(5c),        R^(5d), R^(5e), R^(5f), and R^(5g) is optionally substituted        with one, two, three, four, or five substituents Q, wherein each        substituent Q is independently selected from (a) oxo, cyano,        halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and        heterocyclyl, each of which is further optionally substituted        with one, two, three, or four substituents Q^(a); and (c)        —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),        —C(NR^(a))NR^(b)R^(c), —OC(O)R^(a), —OC(O)OR^(a),        —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),        —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),        —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),        —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),        —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),        —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),        —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a),        R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,        C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is        further optionally substituted with one, two, three, or four        substituents Q^(a); or (iii) R^(b) and R^(c) together with the N        atom to which they are attached form heterocyclyl, which is        further optionally substituted with one, two, three, or four        substituents Q^(a);    -   wherein each Q^(a) is independently selected from the group        consisting of (a) oxo, cyano, halo, and nitro; (h) C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅        aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),        —(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),        —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),        —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),        —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),        —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),        —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),        —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),        —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),        —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e),        R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,        C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and        R^(g) together with the N atom to which they are attached form        heterocyclyl; or    -   wherein two substituents Q that are adjacent to each other        optionally form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or        heterocyclyl, each optionally substituted with one, two, three,        or four substituents Q^(a); and

(ii) an effective amount of a PD-1 or PD-L1 inhibitor.

Embodiment 2. The method of embodiment 1, wherein R^(5b) is (a) halo;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c) —C(O)OR^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c),

Embodiment 3. The method of embodiment 1, wherein R^(5a) and R^(5b) areeach independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

Embodiment 4. The method of embodiment 3, wherein R^(5a) and R^(5b) areeach methyl, optionally substituted with one, two, or three halo(s).

Embodiment 5. The method of any one of embodiments 1-4, wherein n is 1.

Embodiment 6. The method of any one of embodiments 1-5, wherein R^(5f)and R^(5g) are each hydrogen.

Embodiment 7. The method of any one of embodiments 1-4, wherein n is 0.

Embodiment 8. The method of any one of embodiments 1-7, wherein m is 0.

Embodiment 9. The method of any one of embodiments 1-6 or 8, wherein thecompound of Formula (I) is of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one, two, three, or foursubstituents Q^(a).

Embodiment 10. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound I:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 11. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound II:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 12. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound III:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 13. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound IV:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 14. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound V:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 15. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound VI:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 16. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound VII:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 17. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound VIII:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 18. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound IX:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 19. The method of any one of embodiments 1-9, wherein thecompound of Formula (I) is Compound X:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Embodiment 20. The method of any one of embodiments 1-19, wherein thePD-1 or PD-L1 inhibitor is pidilizumab, nivolumab, pembrolizumab,atezolizumab, avelumab, BMS-936559, BGB-A317, PDR001, REGN2810, ordurvalumab, or a variant or biosimilar thereof, or combinations thereof.

Embodiment 21. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is pidilizumab, or a variant or biosimilar thereof.

Embodiment 22. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is nivolumab, or a variant or biosimilar thereof.

Embodiment 23. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is pembrolizumab, or a variant or biosimilar thereof.

Embodiment 24. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is atezolizumab, or a variant or biosimilar thereof.

Embodiment 25. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is BMS-936559, or a variant or biosimilar thereof.

Embodiment 26. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is durvalumab, or a variant or biosimilar thereof.

Embodiment 27. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is BGB-A317, or a variant or biosimilar thereof.

Embodiment 28. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is PDR001, or a variant or biosimilar thereof.

Embodiment 29. The method of embodiment 20, wherein the PD-1 or PD-L1inhibitor is REGN2810, or a variant or biosimilar thereof.

Embodiment 30. The method of any one of embodiments 1-29, wherein thecancer is non-Hodgkin's lymphoma, non-small cell lung cancer, melanoma,renal cell cancer, head and neck cancer, colon cancer, or mesothelioma.

Embodiment 31. The method of any one of embodiments 1-30, wherein thecancer is melanoma.

Embodiment 32. The method of any one of embodiments 1-31, wherein theadministration of compounds occurs in one or more cycles.

Embodiment 33. A method for multiple cycle chemotherapy in a subject,wherein the method comprises administering to the subject at least twochemotherapy cycles, wherein in each chemotherapy cycle, a PI3Kinhibitor and a PD-1 or PD-L1 inhibitor are administered to the subject.

Embodiment 34. The method of embodiment 33, wherein the compounds areadministered within 6 hours or less of each other.

Embodiment 35. The method of either of embodiments 33 or 34, wherein thecompounds are administered within 1 hour or less of each other.

Embodiment 36. The method of any one of embodiments 33-35, wherein thecompounds are administered simultaneously.

Embodiment 37. The method of any one of embodiments 33-35, wherein thecompounds are administered sequentially.

Embodiment 38. The method of any one of embodiments 33-35 or 37, whereinthe PI3K inhibitor is administered before the PD-1 or PD-L1 inhibitor.

Embodiment 39. The method of of any one of embodiments 33-35 or 37,wherein the PI3K inhibitor is administered after the PD-1 or PD-1inhibitor.

Embodiment 40. The method of any one of embodiments 33-39, wherein thePI3K inhibitor is administered orally and the PD-1 or PD-L1 inhibitor isadministered by injection.

Embodiment 41. The method of any one of embodiments 33-40, wherein theadministration of a second cycle is within 50 days of completion of afirst cycle.

Embodiment 42. The method of any one of embodiments 33-40, wherein theadministration of any additional cycle is within 50 days of completionof a previous cycle.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL, (microliters); M (molar); mM (millimolar), μM(micro molar); eq. (equivalent); mmol (millimoles), Hz (Hertz), MHz(megahertz); hr or hrs (hour or hours); min (minutes); and MS (massspectrometry).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Synthesis of Compound I is described in U.S. Pat. No. 9,056,852 B2,which is incorporated by reference for such disclosure.

Example 1 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methylpiperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine,Compound I

A mixture of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(piperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine(80 mg, 0.14 mmol), aq. formaldehyde (37%, 23 mg), and sodiumcyanoborohydride (11 mg, 0.17 mmol) in methanol (2 mL) was stirred atroom temperature for 1 hr. The crude product was purified by prep-HPLCto give compound I (11 mg, 13% yield) as a white solid: 99% purity(HPLC); MS m/z: 577.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, 1H),7.90 (d, 1H), 7.64(t, 1H), 7.42 (m, 2H), 7.32 (d, 7.24(1, 1H), 7.13 (t,1H), 7.07 (d, 1H), 5.15 (s, 1H), 4.00-3.70 (m, 8H), 3.28 (s, 2H), 2.94(m, 2H), 2.78 (m, 2H), 2.28 (s, 3H), 1.89 1.60 (m, 6H), 1.53 (s, 6H)ppm.

Example 2 MC38 Murine Colon Carcinoma Model for Combination of PI3KInhibitor and PD-1 Inhibitor

The combination of a PI3K inhibitor (Compound I) and a PD-1 inhibitor(RPM1-14) was evaluated utilizing a MC38 marine colon carcinomasyngeneic model in female immunocompetent C57BL/6 mice. The study wasdesigned to plot the survival time of murine specimens when treated withthe combination of Compound I and the PD-1 inhibitor.

Compound I dosing solutions were prepared weekly. Formulations ofCompound I were prepared by adding the appropriate amount of 20%VE-TPGS, 80% 100 mM citrate buffer, pH 3.5 solution (vehicle) toCompound I. The resulting suspension was stirred overnight to yield a 5mg/mL dose solution. This solution provided a dosage of 50 mg/kg in adosing volume of 10 mL/kg. The Compound I dosing solution was stored at4° C. when not in use.

The PD-1 inhibitor (anti-PD-1 antibody Clone RMP1-14, Lot No.5792-599016J1) was purchased by CR Discovery Services from Bio X Celland stored at 4° C. upon receipt. Anti-PD-1 antibody dosing solutionswere prepared by diluting aliquots of the stock (6.37 mg/mL) to 0.5mg/mL in sterile PBS, yielding a dosage of 100 μg/animal in a fixeddosing volume of 0.2 mL/animal.

Tumors were measured twice weekly. Treatment response was to beevaluated from tumor growth delay (TGD), the increase in mediantime-to-endpoint (TTE) in treated versus control mice, and fromcomparison of survival curves using logrank analysis. Each animal wasmarked for tumor progression when its tumor reached the 1000 mm³ volumeendpoint, and any animal that did not reach the endpoint was euthanizedat the end of the study and assigned a TTE value equal to the last dayof the study (Day 45).

The median TTE for control Group 1 was 19.0 days, establishing a maximumTGD of 137% for this study. All treatments evaluated in the study wereacceptably-tolerated, with acceptable mean BW losses and notreatment-related (TR) deaths.

Tumor Growth Delay (TGD) Analysis

Animals were monitored individually for tumor growth until Day 45. Thestudy protocol specified a tumor growth delay assay based on the mediantime to endpoint (TTE) in a treated group versus the control group. Eachanimal was marked for tumor progression (TP) when its tumor reached the1000 mm3 volume endpoint. The TTE for each mouse was calculated with thefollowing equation:

${TTE} = \frac{{\log_{10}\left( {{endpoint}\mspace{14mu}{volume}} \right)} - b}{m}$

where b is the intercept and m is the slope of the line obtained bylinear regression of a log-transformed tumor growth data set. The dataset is comprised of the first observation that exceeded the studyendpoint volume and the three consecutive observations that immediatelypreceded the attainment of the endpoint volume. Any animal that did notreach endpoint was euthanized at the end of the study and assigned a TTEvalue equal to the last day of the study (Day 45). In instances in whichthe log-transformed calculated TTE preceded the day prior to reachingendpoint or exceeded the day of reaching tumor volume endpoint, a linearinterpolation was performed to approximate TTE.

On Day 45, MTV (n) was defined as the median tumor volume of the numberof animals, n, that survived to the last day and whose tumors had notreached the volume endpoint. Any animal determined to have died from TRcauses was to be assigned a TTE value equal to the day of death. Anyanimal that died from NTR causes was to be excluded from the analysis.Treatment outcome was evaluated from TGD, which was defined as theincrease in the median TTE for a treatment group compared to the controlgroup:

TGD=T−C

expressed in days, or as a percentage of the median TTE of the controlgroup:

${\%\mspace{14mu}{TGD}} = {\frac{T - C}{C} \times 100}$

where

-   T=median TTE for a treatment group,-   C=median TTE for the control group.

Survival was analyzed by the Kaplan-Meier method. The logrank(Mantel-Cox) and Gehan-Breslow-Wilcoxon tests determined thesignificance of the difference between the overall survival experiences(survival curves) of two groups, based on TTE values. A scatter plot wasconstructed to show TTE values for individual mice, by group. Groupmedian tumor volumes were plotted as functions of time. When an animalexited the study because of tumor size, the final tumor volume recordedfor the animal was included with the data used to calculate the medianvolume at subsequent time points. A Kaplan-Meier plot was constructed toshow the percentage of animals in each group remaining on study versustime.

Example 2a

On Day 1 of the study, four groups of C57BL/6 mice (n=10 for controlgroup and PD-1 monotherapy; n=20 for combination therapy) began dosing.Compound I was administered by oral gavage (p.o.) at a dosage of 50mg/kg in a dosing volume of 10 mL/kg and was adjusted according to themost recent body weight measurement. The PD-1 inhibitor was administeredintraperitoneally (i.p.) at a dosage of 100 μg/animal in a fixed dosingvolume of 0.2 mL/animal.

Group 1 was left untreated and served as the control group for the %TGD.

Group 2 was treated with the PD-1 inhibitor i p. at a dosage of 100μg/animal twice weekly for two weeks.

Group 3 received Compound I p.o. at 50 mg/kg qd×7 starting on Day 1.Beginning on Day 8, this group was then treated with the PD-1 inhibitori.p. at 100 μg/animal biwk×2.

Group 4 received Compound I p.o. at 50 mg/kg qd×7 starting on Day 1.Beginning on Day 8, this group was treated with the PD-1 inhibitor i.p.at 100 μg/animal biwk×2 with the final dose occurring on Day 18. On Day22, treatment with Compound I resumed at 50 mg/kg once daily for fivedays (qd×5, start Day 22).

Group 5 received Compound I p.o. at 50 mg/kg qd×7 starting on Day 1. OnDay 8, these animals received the PD-1 inhibitor i.p. at 100 μg/animalbiwk×2 with the final dose occurring on Day 18. A second course of thePD-1 inhibitor was administered biwk×2 beginning on Day 27.

Group 6 received Compound I p.o. at 50 mg/kg qd×7 starting on Day 1. OnDay 8, these animals received the PD-1 inhibitor i. p. at 100 μg/animalbiwk×2 with the final dose occurring on Day 18. On Day 22, treatmentwith Compound I resumed at 50 mg/kg qd×5. A second course of the PD-1inhibitor was administered biwk×2 beginning on Day 27.

Treatment with Compound I and the PD-1 inhibitor was well-tolerated. Allof the Compound I/PD-1 inhibitor combinations provided statisticallysignificant survival benefits. Combination regimens that administeredCompound I and the PD-1 inhibitor in two chemotherapy cycles were moreeffective than one chemotherapy cycle (Group 6 vs Group 3) and moreeffective than a single cycle of the PD-1 inhibitor (Group 6 vs Group2). The results are depicted in FIG. 1.

Combination regimens that administered Compound I and the PD-1 inhibitorin two chemotherapy cycles were more effective than the administrationof one combination cycle and one Compound I cycle (Group 6 vs Group 4)and more effective than the administration of a single cycle of acombination treatment with Compound 1 and the PD-1 inhibitor, (Group 6vs Group 3). The results are depicted in FIG. 2.

Combination regimens that administered Compound 1 and the PD-1 inhibitorin two chemotherapy cycles were more effective than the administrationone combination cycle and one PD-1 inhibitor cycle (Group 6 vs Group 5)and more effective than the administration of a single cycle of acombination treatment with Compound 1 and the PD-1 inhibitor. (Group 6vs Group 3). The results are depicted in FIG. 3.

What is claimed is:
 1. A method for treating or preventing cancer,comprising administering: (i) an effective amount of a compound ofFormula (I);

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y,and Z are each independently N or CR^(X), with the proviso that at leasttwo of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen or C₁₋₆alkyl; R¹ and R² are each independently (a) hydrogen, cyano, halo, ornitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl; R³ and R⁴ areeach independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ are linkedtogether to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene; R^(5a) is (a) hydrogen or halo;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5b) is (a) halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5c) is—(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or —(CR^(5f)R_(5g))_(n)-heteroaryl;R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5f) and R^(5g) are eachindependently (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl; R⁶ is hydrogen,C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or —SO₂—C₁₋₆ alkyl; m is 0or 1; and n is 0, 1, 2, 3, or 4; wherein each alkyl, alkylene,heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl,cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R¹, R², R³,R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), R^(5c),R^(5d), R^(5e), R^(5f), and R^(5g) is optionally substituted with one,two, three, four, or five substituents Q, wherein each substituent Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one, two, three, or four substituents Q^(a);and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each of which is further optionallysubstituted with one, two, three, or four substituents Q^(a); or (iii)R^(b) and R^(c) together with the N atom to which they are attached formheterocyclyl, which is further optionally substituted with one, two,three, or four substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, and nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(=NR^(e))NR^(f)R^(g),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g),—NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen; (ii) C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heterocyclyl; or wherein two substituents Q thatare adjacent to each other optionally form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each optionally substituted with one,two, three, or four substituents Q^(a); and (ii) an effective amount ofa PD-1 or PD-L1 inhibitor.
 2. The method of claim 1, wherein R^(5b) is(a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 3. The method of claim 1,wherein R^(5a) and R^(5b) are each independently (a) halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R¹,—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),——NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 4. The method of claim 3,wherein R^(5a) and R^(5b) are each methyl, optionally substituted withone, two, or three halo(s).
 5. The method of claim 1, wherein n is
 1. 6.The method of claim 1, wherein R^(5f) and R^(5g) are each hydrogen. 7.The method of claim 1, wherein n is
 0. 8. The method of claim 1, whereinm is
 0. 9. The method of claim 1, wherein the compound of Formula (I) isof Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a) hydrogen,cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachof which is optionally substituted with one, two, three, or foursubstituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or two of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) that are adjacent to each other form C₃₋₁₀cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each optionallysubstituted with one, two, three, or four substituents Q^(a).
 10. Themethod of claim 1, wherein the compound of Formula (I) is Compound I:

or an isotopic variant thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 11. The method of claim 1, whereinthe compound of Formula (I) is Compound II:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 12. The method of claim 1, whereinthe compound of Formula (I) is Compound III:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 13. The method of claim 1, whereinthe compound of Formula (I) is Compound IV:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 14. The method of claim 1, whereinthe compound of Formula (I) is Compound V:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 15. The method of claim 1, whereinthe compound of Formula (I) is Compound VI:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 16. The method of claim 1, whereinthe compound of Formula (I) is Compound VII:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 17. The method of claim 1, whereinthe compound of Formula (I) is Compound VIII:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 18. The method of claim 1, whereinthe compound of Formula (I) is Compound IX:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 19. The method of claim 1, whereinthe compound of Formula (I) is Compound X:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 20. The method of claim 1, whereinthe PD-1 or PD-L1 inhibitor is pidilizumab, nivolumab, pembrolizumab,atezolizumab, avelumab, BMS-936559, BGB-A317, PDR001, REGN2810, ordurvalumab, or a variant or biosimilar thereof, or combinations thereof.21. The method of claim 20, wherein the PD-1 or PD-L1 inhibitor ispidilizumab, or a variant or biosimilar thereof.
 22. The method of claim20, wherein the PD-1 or PD-L1 inhibitor is nivolumab, or a variant orbiosimilar thereof.
 23. The method of claim 20, wherein the PD-1 orPD-L1 inhibitor is pembrolizumab, or a variant or biosimilar thereof.24. The method of claim 20, wherein the PD-1 or PD-L1 inhibitor isatezolizumab, or a variant or biosimilar thereof.
 25. The method ofclaim 20, wherein the PD-1 or PD-L1 inhibitor is BMS-936559, or avariant or biosimilar thereof.
 26. The method of claim 20, wherein thePD-1 or PD-L1 inhibitor is durvalumab, or a variant or biosimilarthereof.
 27. The method of claim 20, wherein the PD-1 or PD-L1 inhibitoris BGB-A317, or a variant or biosimilar thereof.
 28. The method of claim20, wherein the PD-1 or PD-L1 inhibitor is PDR001, or a variant orbiosimilar thereof.
 29. The method of claim 20, wherein the PD-1 orPD-L1 inhibitor is REGN2810, or a variant or biosimilar thereof.
 30. Themethod of claim 1, wherein the cancer is non-Hodgkin's lymphoma,non-small cell lung cancer, melanoma, renal cell cancer, head and neckcancer, colon cancer, or mesothelioma.
 31. The method of claim 1,wherein the cancer is melanoma.
 32. The method of claim 1, wherein theadministration of compounds occurs in one or more cycles.
 33. A methodfor multiple cycle chemotherapy in a subject, wherein the methodcomprises administering to the subject at least two chemotherapy cycles,wherein in each chemotherapy cycle, a PI3K inhibitor and a PD-1 or PD-L1inhibitor are administered to the subject.
 34. The method of clam 33,wherein the compounds are administered within 6 hours or less of eachother.
 35. The method of claim 33, wherein the compounds areadministered within 1 hour or less of each other.
 36. The method ofclaim 33, wherein the compounds are administered simultaneously.
 37. Themethod of claim 33, wherein the compounds are administered sequentially.38. The method of claim 33, wherein the PI3K inhibitor is administeredbefore the PD-1 or PD-L1 inhibitor.
 39. The method of claim 33, whereinthe PI3K inhibitor is administered after the PD-1 or PD-L1 inhibitor.40. The method of claim 33, wherein the PI3K inhibitor is administeredorally and the PD-1 or PD-L1 inhibitor is administered by injection. 41.The method of claim 24, wherein the administration of a second cycle iswithin 50 days of completion of a first cycle.
 42. The method of claim24, wherein the administration of any additional cycle is within 50 daysof completion of a previous cycle.